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WO2025117800A1 - Inhibition of gcpii in the enteric nervous system for visceral pain - Google Patents

Inhibition of gcpii in the enteric nervous system for visceral pain Download PDF

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WO2025117800A1
WO2025117800A1 PCT/US2024/057830 US2024057830W WO2025117800A1 WO 2025117800 A1 WO2025117800 A1 WO 2025117800A1 US 2024057830 W US2024057830 W US 2024057830W WO 2025117800 A1 WO2025117800 A1 WO 2025117800A1
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Barbara Slusher
Diane E. PETERS
Rana RAIS
Pankaj Jay Pasricha
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Johns Hopkins University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/60—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups having oxygen atoms of carbamate groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/002—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Definitions

  • GCPII inhibitors and various agonists/antagonists of ionotropic and metabotropic glutamate receptors have demonstrated analgesic activity in diverse rodent models of both acute and chronic pain, including models of neuropathic pain, cancer pain, burn pain, incisional pain, diabetic neuropathy-induced pain, and inflammatory pain.
  • the ability of GCPII inhibitors to treat visceral pain has not been investigated.
  • the presently disclosed subject matter provides a method for treating visceral pain, the method comprising administering to a subject in need of treatment thereof, a GCPII inhibitor.
  • Representative GCPII inhibitors include, but are not limited to, bile acid conjugates with 2-(phosphonomethyl) pentanedioic acid (2-PMPA), hydroxamate-based GCPII inhibitors and prodrugs thereof, phosphonate-based GCPII inhibitors and prodrugs thereof, L-DOPA, D-DOPA, Caffeic acid, and prodrugs thereof, phosphinate-based GCPII inhibitors, phosphoramidate-based GCPII inhibitors, thiol-based GCPII inhibitors, urea- based GCPII inhibitors, dendrimer conjugates of 2-PMPA, 2-MPPA, and other GCPII inhibitors.
  • the visceral pain includes abdominal pain.
  • the GCPII inhibitor is administered orally.
  • FIG. 1 is a scheme illustrating that GCPII inhibition blocks excess glutamate transmission through a dual mechanism of increasing NAAG (mGluR 3 agonism) and decreasing glutamate;
  • FIG. 2A, FIG. 2B, and FIG. 2C demonstrate that IBD3540 is a potent GCPII inhibitor that is gut-restricted in normal and colitic mice.
  • FIG. 2A shows the chemical structure of IBD3540; a construct containing the GCPII inhibitor 2-(phosphonomethyl)- pentanedioic acid (2-PMPA) conjugated to deoxycholic acid (DCA) via an ester linkage at the C24 position; (FIG.
  • Both IBD3540 (left) and 2- PMPA (right) displayed colon-restricted delivery as evidenced by colon:plasma AUC ratios > 16 under all conditions;
  • FIG. 3A and FIG. 3B show that JHU 241 is a potent GCPII inhibitor.
  • FIG. 3A is the chemical structure of JHU 241, which includes a zinc-binding group (hydroxamic acid) bound to a side chain substituent (benzoate function) via a flexible linker (2-carboxybutyl moiety);
  • FIG. 4 demonstrates that representative GCPII inhibitors, IBD3540 and JHU 241, are analgesic in rat 2,4,6-Trinitrobenzene sulfonic acid (TNBS)-induced chronic visceral hypersensitivity (CVH) model.
  • TNBS 2,4,6-Trinitrobenzene sulfonic acid
  • CVH chronic visceral hypersensitivity
  • FIG. 5 demonstrates that gut-restricted GCPII inhibitor IBD3540 is analgesic in mouse AA-CVH at doses as low as 2.75 mg/kg.
  • FIG. 6 demonstrates that gut-restricted GCPII inhibitor IBD3540 has equal analgesic activity to high-dose gabapentin in AA-CVH.
  • FIG. 7 demonstrates that repeated oral administration of (S)-IBD3540 retains analgesic efficacy in AA-CVH.
  • neonatal mice were sensitized with diluted acetic acid or saline followed by randomization to experimental groups at 4-6 months of age.
  • Visceral pain describes pain emanating from the internal thoracic, pelvic, or abdominal organs.
  • visceral pain is associated with the viscera, which encompasses the organs of the abdominal cavity, including the sex organs, spleen, and parts of the digestive system.
  • Visceral structures are highly sensitive to distension (stretch), ischemia, and inflammation.
  • Visceral pain can originate from an ongoing injury to the internal organs or the tissues that support them or can arise as secondary to a disease, disorder, or condition of an internal organ.
  • Visceral pain is often vague and can be described as a deep ache, pressure, gnawing, twisting, colicky, or dull.
  • Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus, such as organ distension.
  • visceral pain originates in the organs of the chest, abdomen, or pelvis it also may be felt it in other areas of the body. Visceral pain can be accompanied by other symptoms including, but not limited to, nausea, vomiting, sweating, a racing heart, and changes in other vital signs. Common causes of visceral pain include, but are not limited to, inflammation, menstrual cramps, swelling and stretching of the organs, blockage, particularly of the bowels or urethra, decreased blood flow and tumors, particularly when concentrated in the pelvis or abdomen.
  • Visceral pain also can result from one or more conditions selected from a urogenital disorder, including conditions affecting the urinary tract and/or the genital tract, i.e., reproductive organs; a urologic disorder, including conditions affecting the urinary tract, i.e.
  • kidneys, ureters, or bladder such as bladder neoplasm, chronic urinary tract infection, interstitial cystitis, radiation cystitis, recurrent cystitis, recurrent urethritis, urolithiasis, uninhibited bladder contractions (detrusor-sphincter dyssynergia), urethral diverticulum, chronic urethral syndrome, urethral carbuncle, and urethral stricture; a genital disorder, including conditions affecting the genital tract, such as testicular torsion, prostatitis, and Peyronie’s disease. Visceral pain is a prevalent, debilitating condition with limited treatment options and thus remains a major clinical problem.
  • the presently disclosed subject matter provides GCPII inhibitors for use in treating visceral pain, including abdominal pain.
  • glutamatergic signaling pathways have received lesser characterization in the enteric nervous system (ENS), all subtypes of mGluRs and iGluRs present in the CNS/PNS have been identified in mammalian gastrointestinal tissues.
  • GCPII inhibitors generally fall into the following representative classes including, but not limited to, phosphonates, including bile acid conjugates of phosphonates, such as 2- PMPA, phosphinates, phosphoramidates, thiols, hydroxamates, and ureas:
  • GCPII inhibitors representative of these general classes include 2- (phosphonomethyl) pentanedioic acid (2-PMPA) (phosphonates), 2-(3- mercaptopropyl)pentanedioic acid (2-MPPA) (thiols), 2-(2-(hydroxyamino)-2- oxoethyl)pentanedioic acid (JHU 241) (hydroxamates), see also Rais et al., 2017, for other hydroxamate-based glutamate GCPII inhibitors, including, 4-carboxy-alpha-[3- (hydroxyamino)-3-oxopropyl]-benzenepropanoic acid, and N-[N-[(S)]-1,3-dicarboxypropyl] carbamoyl]-L-leucine (ZJ-43) (ureas):
  • Other phosphonate-based GCPII inhibitors include GPI-5232, Jackson and Slusher, 2001, and
  • the presently disclosed GCPII inhibitors can be formed by conjugating the potent GCPII inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) to a bile acid.
  • the chemical formula of 2-PMPA is provided immediately herein below: (2-PMPA).
  • Bile acids, which are abundant endogenously, were selected as the conjugate as they also are reported to have direct immunomodulatory effects in a variety of inflammatory models, Sipka and Bruckner, 2014; Calmus and Poupon, 2014; Ho and Steinman, 2016, including protection in IBD models. Laukens, et al., 2014.
  • Bile acids have the following general chemical structure: wherein: R'1 and R'2 are each independently H or -OH; R' 3 is -OH; R'4 is selected from the group consisting of -OH, -NHCH 2 COOH, and -NHCH 2 CH 2 SO3H; and salts thereof.
  • Representative bile acids include, but are not limited to, cholic acid, glycocholic acid, deoxycholic acid, lithocholic acid, glycodeoxycholic acid, chenodeoxycholic acid (also referred to as chenocholic acid), glycochenodeoxycholic acid, ursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, and derivatives thereof, the structures of which are provided immediately herein below in Table 1.
  • Table 1 Representative Bile Acids Table 1.
  • Representative Bile Acids Table 1.
  • Representative Bile Acids ovides a conjuga te of 2-(phosphonomethyl) pentanedioic acid (2-PMPA), or a derivative thereof, and a bile acid, or derivative thereof.
  • the compound of formula (I) is selected from the group consisting of:
  • the compound of formula (I) is selected from the group consisting of:
  • Hydroxamate-based GCPII Inhibitors and Prodrugs thereof Hydroxamate-based GCPII inhibitors include 2-(2-(hydroxyamino)-2- oxoethyl)pentanedioic acid (JHU 241) and 4-carboxy-alpha-[3-(hydroxyamino)-3- oxopropyl]-benzenepropanoic acid. See Stoermer et al., 2003; Novakova et al., 2016; and Rais et al., 2017, for other hydroxamate-based glutamate GCPII inhibitors.
  • the GCPII inhibitor is a hydroxamate-based GCPII inhibitor of formula (IIa): wherein n is an integer selected from 0, 1, 2, and 3.
  • the hydroxamate-based GCPII inhibitor comprises: Representative prodrugs of hydroxamate-based GCPII inhibitors are disclosed in International PCT Patent Application Publication No. WO2018094334 for Prodrugs of Hydroxamate-Based GCPII Inhibitors, to Slusher et al., published May 24, 2018, which is incorporated herein by reference in its entirety, in particular, page 6, line 31, through page 17, line 1; U.S. Patent No.
  • the compound of formula (IIb) is selected from the group consisting of: wherein R 2 , R 3 , and R 4 , are as defined hereinabove; and stereoisomers and pharmaceutically acceptable salts thereof.
  • R 2 is as defined hereinabove;
  • R 3 is selected from the group consisting of H and substituted and unsubstituted C 1 -C 6 alkyl;
  • n is 1;
  • R 5 andR 6 are H;
  • Ar is phenyl;
  • R 9 is selected from the group consisting of substituted C 1 -C 3 alkyl, and unsubstituted C 1 -C 3 alkyl
  • the compound of formula (IIb) is selected from the group consisting of:
  • R 2 is -(CR 5 R 6 ) n -R 7 , n is 1, and R 7 is substituted C 3 -C 12 cycloheteroalkenyl.
  • the compound of formula (IIb) is selected from the group consisting of:
  • R 7 is unsubstituted C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, unsubstituted C 6 -C 12 aryl, or unsubstituted C 6 -C 12 aralkyl.
  • the compound of formula (IIb) is selected from the group consisting of:
  • R 7 is unsubstituted C 1 -C 6 alkyl.
  • the GCPII inhibitor is 2-PMPA or a prodrug thereof.
  • Representative prodrugs of 2-PMPA are disclosed in International PCT Patent Application Publication No. WO2016022827 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., published February 11, 2016, which is incorporated by reference in its entirety, in particular page 9, line 19, through page 25, line 12.
  • the compound of formula (IIIa) is selected from the group consisting of: In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of: , , and . In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of: In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of: In particular embodiments, the compound of formula (IIIa) is: In particular embodiments, the compound of formula (IIIa) is: In particular emb odiments, the compound of formula (IIIa) is: In particular embodiments, the compound of formula (IIIa) is: In particular embodiments, the compound of formula (IIIa) is: In particular embodiments, the compound of formula (IIIa) is: In particular embodiments, the compound of formula (IIIa) is: In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of: In particular embodiments, the compound of formula (IIIa) is: In partic ular embodiments, the compound of formula (IIIa) is:
  • the compound of formula (IIIa) is: .
  • the compound of formula (IIIa) is In part icular embodiments, the compound of formula (IIIa) is In particular embodiments, the compound of formula (IIIa) is: In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of: In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of: In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of: In particular embodiments, the compound of formula (IIIa) is: In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of: , and .
  • 2-PMPA prodrugs are disclosed in: U.S. Patent No. 10,544,176 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., issued January 28, 2020; U.S. Patent No. 9,988,407 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., issued June 5, 2018; U.S. Patent Application Publication No. US 2020-0399298 A1 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., published December 24, 2020, each of which is incorporated herein by reference in its entirety.
  • phosphonate-based GCPII inhibitors include GPI-5232, Jackson and Slusher, 2001, and VA-033, Ding et al., 2004: D. L-DOPA, D-DOPA, Caffeic acid, and Prodrugs Thereof
  • the presently disclosed subject matter provides L-DOPA, D- DOPA, caffeic acid, and prodrugs thereof as GCPII inhibitors.
  • Representative prodrugs of L- DOPA, D-DOPA, and caffeic acid are disclosed in International PCT Patent Application Publication No. WO2023064783 for DOPA and Caffeic Acid Analogs As Novel GCPII Inhibitors, to Rais et al., published April 20, 2023, which is incorporated herein by reference in its entirety.
  • R 1 is: -OR 5 , wherein R 5 is selected from the group consisting of H, C 1 -C 8 alkyl, and -O- (CH 2 ) n -R 6 , wherein n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8 and R 6 is substituted or unsubstituted aryl or heteroaryl; or -NR 7 R8, wherein R 7 and R8 are each independently selected from the group consisting of H, C 1 -C 4 alkyl, C3-C6 cycloalkyl, C 1 -C 8 alkoxyl, unsubstituted or substituted aryl or heteroaryl, -(CH 2 ) m -R 9 , wherein R 9 is -OR 10 or CHX
  • R 1 is -OR 5 , and R 5 is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec- pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, and n-octyl.
  • R 1 is -OR 5 , and R 5 is H or -O-(CH 2 ) n -R 6 , wherein R 6 is substituted or unsubstituted phenyl.
  • R 1 is -NR 7 R 8 , and R 7 is H or C 1 -C 4 alkyl and R 8 is selected from the group consisting of H, C 1 -C 4 alkyl, C3-C6 cycloalkyl, unsubstituted or substituted phenyl, -(CH 2 ) m -R 9 , wherein R 9 is -OR 1 0 or CHX2, wherein R 1 0 is H or C 1 -C 4 alkyl, and each X is halogen, and -(CH 2 ) m -CH(NH 2 )(COOH), wherein each m is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.
  • R 3 and R4 are each H. In certain embodiments, if R 1 is -OR 5 , then R 5 cannot be H.
  • the compound of formula (IV) is selected from the group consisting of:
  • phosphinate-based GCPII inhibitors include, but are not limited to: 2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[((2-phenylethyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid;
  • Phosphoramidate-based GCPII inhibitors include compounds of formula (V): Representative phosphoramidate-based GCPII inhibitors are disclosed in Ferraris et al., 2012, and include compounds of formula (V’): wherein R is H or C 1 -C 4 alkyl, and R’ is benzyl; or a compound of formula (V”): wherein R is selected from H, 4-fluorobenzoyl, and 6-(fluorescein-5-carboxamido)hexanoyl. G.
  • Thiol-based GCPII Inhibitors include 3-(2-mercaptoethyl)biphenyl- 2,3-dicarboxylic acid (E2072) and GPI-5693: See Wozniak et al., 2012b; Slusher et al., 2001. Other thiol-based are provided in Ba ⁇ inka et al., 2012, and International Patent Application No. WO2002057222 for Thiol-Based NAALADASE Inhibitors, to Tsukamoto et al., published July 25, 2002, which is incorporated herein by reference in its entirety. H.
  • Urea-based GCPII Inhibitors include MIP-1555, MIP-1519, MIP-1545, MIP-1427, MIP-1428, MIP-1379, MIP-1072, MIP-1095, MIP-1558, MIP-1405, and MIP-1404. See U.S. Patent No. 11,167,049, for Organ protection in PSMA-targeted radionuclide therapy of prostate cancer, to Babich et al., issued Nov. 9, 2021, which is incorporated herein by reference in its entirety.
  • urea-based GCPII inhibitors include PSMA I&T, Weineisen et al., 2015, PSMA-617, Bene ⁇ ová et al., 2015, PSMA-11, Eder et al., 2012, DCIBzL, Chen et al., 2008, 18 F-DCFPyl, Chen et al., 2011, ZJ 38, GCPII-IN-1, and JB-352, Knedl ⁇ k et al., 2017:
  • the presently disclosed subject matter provides dendrimer conjugates of 2-PMPA, 2-MPPA, and other GCPII inhibitors and their use treating visceral pain.
  • the dendrimers are in the form of dendrimer nanoparticles comprising poly(amidoamine) (PAMAM) hydroxyl-terminated dendrimers covalently linked, for example to 2-PMPA, 2-MPPA, or another GCPII inhibitor.
  • PAMAM poly(amidoamine)
  • Representative dendrimer compositions suitable for use with the presently disclosed methods are disclosed in International PCT Patent Application Publication No.
  • the dendrimer nanoparticles include one or more ethylene diamine-core PAMAM hydroxyl-terminated generation-4 through generation-10 (e.g., ⁇ G4- OH) dendrimers covalently linked to 2-PMPA.
  • the term “dendrimer” includes, but is not limited to, a molecular architecture having an interior core, interior layers (or “generations”) of repeating units regularly attached to the interior core, and an exterior surface of terminal groups attached to the outermost generation.
  • Dendrimers suitable for use with the presently disclosed methods include, but are not limited to, polyamidoamine (PAMAM), polypropyiamine (POPAM), poly(propylene imine) (PPI), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), and/or aromatic polyether dendrimers.
  • PAMAM polyamidoamine
  • POPAM polypropyiamine
  • PPI poly(propylene imine)
  • PEPI polyethylenimine
  • polylysine polylysine
  • polyester iptycene
  • aliphatic poly(ether) and/or aromatic polyether dendrimers e.g., the first dendrimer may include a PAMAM dendrimer, while the second dendrimer may comprise a POPAM dendrimer.
  • the first or second dendrimer may further include an additional agent.
  • a multiarm PEG polymer can include a polyethylene glycol having at least two branches bearing sulfhydryl or thiopyridine terminal groups; however, embodiments disclosed herein are not limited to this class and PEG polymers hearing other terminal groups, such as succinimidyl or maleimide terminal groups, can be used.
  • PEG polymers in the molecular weight 10 kDa to 80 kDa can be used.
  • the dendrimer complex can include multiple dendrimers.
  • the dendrimer complex can include a third dendrimer; wherein the third- dendrimer is complexed with at least one other dendrimer.
  • a third agent can be complexed with the third dendrimer.
  • the first and second dendrimers are each complexed to a third dendrimer, wherein the first and second dendrimers are PAMAM dendrimers and the third dendrimer is a POPAM dendrimer. Additional dendrimers also can be incorporated. When multiple dendrimers are used, multiple agents also can be incorporated. This characteristic is not limited by the number of dendrimers complexed to one another.
  • PAMAM dendrimer refers to a poly(amidoamine) dendrimer, which may contain different cores, with amidoamine building blocks.
  • the method for making them is known to those of skill In the art and generally, involves a two-step iterative reaction sequence that produces concentric shells (i.e., “generations”) of dendritic ⁇ -alanine units around a central interior core.
  • This PAMAM core-shell architecture grows linearly in diameter as a function of added shells (generations).
  • the surface groups amplify exponentially at each generation according to dendritic-branching mathematics.
  • Such dendrimers are available in generations G0 - G10 with 5 different core types and 10 functional surface groups.
  • the PAMAM dendrimers can have carboxylic, amine and hydroxyl terminal groups and can be any generation of dendrimers including, but not limited to, generation 1 PAMAM dendrimers, generation 2 ⁇ A ⁇ dendrimers, generation 3 PAMAM dendrimers, generation 4 PAMAM dendrimers, generation 5 PAMAM dendrimers, generation 6 PAMAM dendrimers, generation 7 PAMAM dendrimers, generation 8 PAMAM dendrimers, generation 9 PAMAM dendrimers, or generation 10 PAMAM dendrimers.
  • the PAMAM dendrimers can be generation 4 dendrimers, or more, with hydroxyl groups attached to their functional surface groups.
  • Dendrimer complexes can be formed by covalently bonding or otherwise attaching, e.g., via intermolecularly dispersion or encapsulation, a therapeutically active agent, e.g., 2- PMPA, to a dendrimer or multiarm PEG.
  • a therapeutically active agent e.g., 2- PMPA
  • the attachment can occur via an appropriate spacer that provides a disulfide bridge between the agent and the dendrimer.
  • the dendrimer complexes are capable of rapid release of the agent in vivo by thiol exchange reactions, under the reduced conditions found in a body.
  • the term “spacers” as used herein is intended to include compositions used for linking a therapeutically active agent to the dendrimer.
  • the spacer can be either a single chemical entity or two or more chemical entities linked together to bridge the polymer and the therapeutic agent or imaging agent.
  • the spacers can include any small chemical entity, peptide or polymers having sulfhydryl, thiopyridine, succinimidyl, maleimide, vinylsulfone, and carbonate terminal groups.
  • the spacer can comprise thiopyridine terminated compounds including, but not limited to, dithiodipyridine, N-succinimidyl 3-(2-pyridyldithio)- propionate (SPDP), succinimidyl 6-(3-[2-pyridyldithio]-propionamido)hexanoate LC-SPDP, or Sulfo-LC-SPDP.
  • thiopyridine terminated compounds including, but not limited to, dithiodipyridine, N-succinimidyl 3-(2-pyridyldithio)- propionate (SPDP), succinimidyl 6-(3-[2-pyridyldithio]-propionamido)hexanoate LC-SPDP, or Sulfo-LC-SPDP.
  • the spacer also can include peptides wherein the peptides are linear or cyclic having sulfhydryl groups, such as glutathione, homocysteine, cysteine and its derivatives, arg-gly-asp-cys (RGDC), cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)), cyclo(Arg-Gly-Asp-D-Tyr-Cys), cyelo(Arg-Ala-Asp-d-Tyr-Cys).
  • RGDC arg-gly-asp-cys
  • c(Arg-Gly-Asp-d-Phe-Cys) cyclo(Arg-Gly-Asp-D-Tyr-Cys)
  • cyelo(Arg-Ala-Asp-d-Tyr-Cys cyelo(Arg-Ala-
  • the spacer can be a mercapto acid derivative such as 3-mercapto propionic acid, mercapto acetic acid, 4- mercapto butyric acid, thiolan-2-one, 6-mercaptohexanoic acid, 5-mercapto valeric acid and other mercapto derivatives such as 2-mercaptoethanol and 2-mercaptoethylamine.
  • the spacer can be thiosalicyclic acid and its derivatives including (4-succinimidyloxycarbonyl- methyl- ⁇ -2-pyridylthio)toluene and (3-[2-pyridithio]propionyl hydrazide.
  • the spacer can have maleimide terminal groups wherein the spacer comprises polymer or small chemical entity, such as bis-maleimido diethylene glycol and bis-maleimido triethylene glycol, bismaleimidoethane, bismaleimidohexane.
  • the spacer can comprise a vinylsulfone, such as 1,6-hexane-bis-vinylsulfone.
  • the spacer can comprise thioglycosides, such as thioglucose.
  • the spacer can be a reduced protein, such as bovine serum albumin and human serum albumin, or any thiol terminated compound capable of forming disulfide bonds.
  • the spacer can include polyethylene glycol having maleimide, succinimidyl and thiol terminal groups.
  • the GCPII inhibitor includes: (S)-2-((N-((S)-1,2-dicarboxyethyl)sulfamoyl)amino)pentanedioic acid: (S)-2-((((S)-5-(4-bromo-2-fluorobenzamido)-1-carboxypentyl)carbamoyl)oxy)pentanedioic acid: (S)-2-((S)-1-carboxy-3-methylbutylcarbamoyloxy)pentanedioic acid: Accordingly, in some embodiments, the presently disclosed subject matter provides a method for treating visceral pain, the method comprising administering to a subject in need of treatment thereof, a GCPII inhibitor disclosed herein.
  • method of treatment lessens the severity of visceral pain in the subject.
  • the visceral pain includes abdominal pain.
  • the visceral pain is associated with pain originating from one or more organs selected from the stomach, bladder, uterus, rectum, and combinations thereof.
  • the visceral pain includes visceral pain from abdominoplasty.
  • the visceral pain is acute visceral pain.
  • the visceral pain is chronic visceral pain.
  • the GCPII inhibitor is administered orally.
  • the visceral pain is associated with an elevated level of GCPII in the subject in need of treatment compared to a control subject not afflicted with the condition, disease, or disorder.
  • the term “elevated,” as in “an elevated level of GCPII,” refers to a level of GCPII in a subject having or suspected of having a disease, disorder, or condition associated with an elevated level of GCPII compared to a level of GCPII in a normal subject, i.e., a subject who does not have or is not suspected of having a disease, disorder, or condition associated with an elevated level of GCPII, such as an increase of approximately 50%, 100%, 200%, 300%, 400%, 500%, or more.
  • performing the presently disclosed method results in inhibiting GCPII activity in a subject.
  • the term “inhibit” means to decrease or diminish the nSMase2 activity found in a subject, e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 985, 99%, or 100% of the nSMase2 activity compared to an untreated control subject or a subject without the disease or disorder.
  • inhibitor also may mean to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease, disorder
  • treating can include reversing, alleviating, inhibiting the progression of, preventing, or reducing the likelihood of the disease, disorder, or condition to which such term applies, or one or more symptoms or manifestations of such disease, disorder, or condition.
  • Preventing refers to causing a disease, disorder, condition, or symptom or manifestation of such, or worsening of the severity of such, not to occur.
  • the presently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition.
  • a “subject” treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term “subject.” Accordingly, a “subject” can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes.
  • Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like.
  • mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; cap
  • an animal may be a transgenic animal.
  • the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects.
  • a “subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease.
  • the terms “subject” and “patient” are used interchangeably herein.
  • the term “subject” also refers to an organism, tissue, cell, or collection of cells from a subject.
  • the “effective amount” of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response.
  • the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the makeup of the pharmaceutical composition, the target tissue, and the like.
  • the term “combination” is used in its broadest sense and means that a subject is administered at least two agents, more particularly a compound disclosed herein and at least one other therapeutic agent. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of a, e.g., single disease state.
  • the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days.
  • the active agents are combined and administered in a single dosage form.
  • the active agents are administered in separate dosage forms (e.g., wherein it is desirable to vary the amount of one but not the other).
  • the single dosage form may include additional active agents for the treatment of the disease state.
  • the compounds disclosed herein can be administered alone or in combination with adjuvants that enhance stability of the compounds, alone or in combination with one or more therapeutic agents, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients.
  • combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
  • the timing of administration of a compound disclosed herein and at least one additional therapeutic agent can be varied so long as the beneficial effects of the combination of these agents are achieved.
  • the phrase “in combination with” refers to the administration of a compound described herein and at least one additional therapeutic agent either simultaneously, sequentially, or a combination thereof. Therefore, a subject administered a combination of a compound described herein and at least one additional therapeutic agent can receive a compound and at least one additional therapeutic agent at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in either order, on the same day or on different days), so long as the effect of the combination of both agents is achieved in the subject.
  • the agents can be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer of one another. In other embodiments, agents administered sequentially, can be administered within 1, 5, 10, 15, 20 or more days of one another.
  • the compound described herein and at least one additional therapeutic agent are administered simultaneously, they can be administered to the subject as separate pharmaceutical compositions, each comprising either a compound or at least one additional therapeutic agent, or they can be administered to a subject as a single pharmaceutical composition comprising both agents.
  • the effective concentration of each of the agents to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent.
  • the effects of multiple agents may, but need not be, additive or synergistic.
  • the agents may be administered multiple times. In some embodiments, when administered in combination, the two or more agents can have a synergistic effect.
  • the terms “synergy,” “synergistic,” “synergistically” and derivations thereof, such as in a “synergistic effect” or a “synergistic combination” or a “synergistic composition” refer to circumstances under which the biological activity of a combination of a compound described herein and at least one additional therapeutic agent is greater than the sum of the biological activities of the respective agents when administered individually.
  • Synergy can be expressed in terms of a “Synergy Index (SI),” which generally can be determined by the method described by F. C.
  • a “synergistic combination” has an activity higher that what can be expected based on the observed activities of the individual components when used alone.
  • a “synergistically effective amount” of a component refers to the amount of the component necessary to elicit a synergistic effect in, for example, another therapeutic agent present in the composition.
  • the “agent(s)” may be formulated into liquid or solid dosage forms and administered systemically or locally. The agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art.
  • Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, intra-sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
  • the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
  • aqueous solutions such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art.
  • Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the disclosure into dosages suitable for systemic administration is within the scope of the disclosure.
  • the compositions of the present disclosure in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject (e.g., patient) to be treated.
  • the agents of the disclosure also may be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances, such as saline; preservatives, such as benzyl alcohol; absorption promoters; and fluorocarbons.
  • the compound disclosed herein is administered intranasally in a form selected from the group consisting of a nasal spray, a nasal drop, a powder, a granule, a cachet, a tablet, an aerosol, a paste, a cream, a gel, an ointment, a salve, a foam, a paste, a lotion, a cream, an oil suspension, an emulsion, a solution, a patch, and a stick.
  • the term administrating via an "intranasal route” refers to administering by way of the nasal structures.
  • Pharmaceutical compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose.
  • the compounds according to the disclosure are effective over a wide dosage range.
  • dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • a non-limiting dosage is 10 to 30 mg per day.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone).
  • disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
  • PEGs liquid polyethylene glycols
  • stabilizers may be added.
  • compositions thereof include pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and include salts of active compounds that can be prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein.
  • the parent form of the compound can differ from the various salt forms in certain physical properties, such as solubility, and the like.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent or by ion exchange, whereby one basic counterion (base) in an ionic complex is substituted for another.
  • Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium, and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange, whereby one acidic counterion (acid) in an ionic complex is substituted for another.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, organic acids, and amino acids. See, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • salts suitable for use with the presently disclosed subject matter include, by way of example but not limitation, acetate, arginate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, monohydrogencarbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, galactonate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydriodic, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, me
  • hydrocarbon refers to any chemical group comprising hydrogen and carbon. A hydrocarbon group may be substituted or unsubstituted. As would be known to one of ordinary skill in the art, all valencies must be satisfied in making any substitutions.
  • the hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl”, “cycloaliphatic”, or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 alipatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.
  • alkane refers to acyclic branched or unbranched hydrocarbons having the general formula C n H 2n+2 , and therefore consisting entirely of hydrogen atoms and saturated carbon atoms.
  • alkyl refers to a univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom and having the chemical formula of -C n H 2n+1 .
  • the groups derived by removal of a hydrogen atom from a terminal carbon atom of unbranched alkanes form a subclass of normal alkyl (n-alkyl) groups H(CH 2 ) n .
  • RCH 2 , R 2 CH (R ⁇ H), and R 3 C (R ⁇ H) are primary, secondary and tertiary alkyl groups, respectively.
  • An alkyl can be a straightchain (i.e., unbranched) or branched acyclic hydrocarbon having the number of carbon atoms designated (i.e., C1-10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons).
  • the term “alkyl” refers to C 1-20 inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons.
  • the alkyl can be a C 1 -C 4 alkyl, including 1, 2, 3, and 4 carbons.
  • the alkyl can be a C 1 -C 6 alkyl, including 1, 2, 3, 4, 5, and 6 carbons. In even yet other embodiments, the alkyl can be a C 1 -C 8 alkyl, including 1, 2, 3, 4, 5, 6, 7, and 8 carbons. “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C 1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • alkyl refers to straight-chain alkyls. In other embodiments, “alkyl” refers to branched alkyls. In certain other embodiments, “alkyl” refers to straight-chain and/or branched alkyls. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, and dodecyl.
  • Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more substituents, which can be the same or different.
  • substituent groups include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, halogen, acyl, carboxyl, oxo, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain having from 1 to 20 carbon atoms or heteroatoms consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
  • cycloalkane refers to saturated monocyclic hydrocarbons (with or without side chains), e.g., cyclobutane.
  • Unsaturated monocyclic hydrocarbons having one endocyclic double or one triple bond are called cycloalkenes and cycloalkynes, respectively. Those having more than one such multiple bond are cycloalkadienes, cycloalkatrienes, and the like.
  • cyclic hydrocarbons having any number of such multiple bonds are cyclic olefins or cyclic acetylenes.
  • cycloalkyl refer to a univalent group derived from a cycloalkane by removal of a hydrogen atom from a ring carbon atom. Cycloalkyls can be a mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group also can be optionally substituted with a substituent group provided hereinabove for alkyl groups.
  • Representative monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, and fused ring systems, such as dihydro- and tetrahydronaphthalene, and the like.
  • cycloalkylalkyl refers to a cycloalkyl group, which is attached to the parent molecular moiety through an alkylene moiety, also as defined above, e.g., a C 1-20 alkylene moiety.
  • alkylene moiety also as defined above, e.g., a C 1-20 alkylene moiety.
  • Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
  • cycloheteroalkyl and “heterocycloalkyl” (or more generally “heterocyclic”) are used interchangeably and refer to an unsaturated ring system, such as a 3- to 10-member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), in which the nitrogen, sulfur, and phosphorus heteroatoms may be oxidized and the nitrogen heteroatom may be quaternized.
  • an unsaturated ring system such as a 3- to 10-member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), in which the nitrogen, sulfur, and phosphorus heteroatoms may be
  • the cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings.
  • Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.
  • cycloalkylene and heterocycloalkylene refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.
  • the terms “bicycloalkyl” and “bicycloheteroalkyl” refer to two cycloalkyl or cycloheteroalkyl groups that are bound to one another. Non-limiting examples include bicyclohexane and bipiperidine.
  • An “unsaturated hydrocarbon” has one or more double bonds or triple bonds.
  • alkene refers to an acyclic branched or unbranched hydrocarbons having one carbon–carbon double bond and the general formula C n H 2n .
  • Acyclic branched or unbranched hydrocarbons having more than one double bond are alkadienes, alkatrienes, and the like. More particularly, the term “alkenyl” as used herein refers to a monovalent group derived from a C2-20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule.
  • Alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), 2-propenyl, butenyl, 1-methyl-2-buten-1- yl, pentenyl, 2-isopentenyl, hexenyl, octenyl, allenyl, butadienyl, crotyl (but-2-en-1-yl), 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), and the like, including higher homologs and isomers.
  • cycloalkenyl refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond.
  • cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3- cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
  • alkyne refers to an acyclic branched or unbranched hydrocarbons having a carbon-carbon triple bond and the general formula CnH2n-2, RC ⁇ CR.
  • Acyclic branched or unbranched hydrocarbons having more than one triple bond are known as alkadiynes, alkatriynes, and the like.
  • alkynyl refers to a monovalent group derived from a straight or branched C2-20 hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond.
  • alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, and the like.
  • alkylene refers to an alkanediyl group having the free valencies on adjacent carbon atoms, e.g.
  • alkylene by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • the alkylene group can be straight, branched or cyclic.
  • the alkylene group also can be optionally unsaturated and/or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described.
  • An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • heteroalkylene by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • arene refers to a monocyclic and polycyclic aromatic hydrocarbon.
  • aryl refers to a group derived from arenes by removal of a hydrogen atom from a ring carbon atom. Groups similarly derived from heteroarenes are sometimes subsumed in this definition.
  • An aryl group can include, for example, a single ring or multiple rings (such as from 2 to 3 rings), which are fused together or linked covalently.
  • heteroaryl refers to the class of heterocyclyl groups derived from heteroarenes by removal of a hydrogen atom from any ring atom.
  • a “heteroaryl” group can include from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,
  • arylene and “heteroarylene” refer to the divalent forms of aryl and heteroaryl, respectively.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl and heteroarylalkyl are meant to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like.
  • haloaryl as used herein is meant to cover only aryls substituted with one or more halogens.
  • a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g. “3 to 7 membered”), the term “member” refers to a carbon or heteroatom.
  • members refers to a carbon or heteroatom.
  • acyl specifically includes arylacyl groups, such as a 2-(furan-2- yl)acetyl)- and a 2-phenylacetyl group.
  • acyl groups include acetyl and benzoyl.
  • alkoxyl or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl–O–) or unsaturated (i.e., alkenyl–O– and alkynyl–O–) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C1-20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n- pentoxyl, neopentoxyl, n-hexoxyl, and the like.
  • alkoxyalkyl refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group.
  • Aryloxyl refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl.
  • aryloxyl as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
  • “Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl.
  • Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
  • “Aralkyloxyl” refers to an aralkyl-O– group wherein the aralkyl group is as previously described.
  • An exemplary aralkyloxyl group is benzyloxyl, i.e., C 6 H 5 -CH 2 -O-.
  • An aralkyloxyl group can optionally be substituted.
  • Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert- butyloxycarbonyl.
  • Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.
  • An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
  • acyloxyl refers to an oxygen-centered radicals consisting of an acyl radical bonded to an oxygen atom, e.g., an acyl-O- group wherein acyl is as previously described.
  • amine refers to a compound formally derived from ammonia by replacing one, two or three hydrogen atoms by hydrocarbyl groups, and having the general structures RNH2 (primary amines), R 2 NH (secondary amines), R 3 N (tertiary amines). In some embodiments, the term amino refers to the –NH 2 group.
  • the amino group is -NR'R”, wherein R' and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R' and R are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • acylamino and “alkylamino” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.
  • alkylamino, dialkylamino, and trialkylamino refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
  • alkylamino refers to a group having the structure –NHR’ wherein R’ is an alkyl group, as previously defined;
  • dialkylamino refers to a group having the structure –NR’R”, wherein R’ and R” are each independently selected from the group consisting of alkyl groups.
  • trialkylamino refers to a group having the structure –NR’R”R”’, wherein R’, R”, and R’” are each independently selected from the group consisting of alkyl groups. Additionally, R’, R”, and/or R’” taken together may optionally be —(CH 2 ) k – where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.
  • alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl–S–) or unsaturated (i.e., alkenyl–S– and alkynyl–S–) group attached to the parent molecular moiety through a sulfur atom.
  • thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • “Acylamino” refers to an acyl-NH– group wherein acyl is as previously described.
  • “Aroylamino” refers to an aroyl-NH– group wherein aroyl is as previously described.
  • cyano refers to the -C ⁇ N group.
  • halo refers to fluoro, chloro, bromo, and iodo groups. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C1-4)alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.
  • hydroxyl refers to the –OH group.
  • hydroxyalkyl refers to an alkyl group substituted with an –OH group.
  • mercapto refers to the –SH group.
  • keto is sometimes used as a prefix, but such use has been abandoned by IUPAC for naming specific compounds.
  • oxo as used herein means an oxygen atom that is double bonded to a carbon atom or to another element.
  • nitro refers to the –NO2 group.
  • thiol refers to a compounds having the structure RSH (R ⁇ H), e.g., MeCH 2 SH ethanethiol.
  • RSH R ⁇ H
  • a thiol also is known by the term “mercaptan.”
  • thiohydroxyl or thiol refers to a group of the formula – SH.
  • sulfate refers to the –SO4 group.
  • sulfide refers to a compound having the structure RSR (R ⁇ H) and also are referred to as “thioethers.”
  • ureido refers to a urea group of the formula –NH—CO—NH2.
  • a structure represented generally by, for example, the formula: as used herein refers to a ring structure, for example, but not limited to a 3-carbon, a 4- carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and/or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure.
  • n is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution.
  • Each R group if more than one, is substituted on an available carbon of the ring structure rather than on another R group.
  • the structure above where n is 0 to 2 would comprise compound groups including, but not limited to: and the like.
  • a dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring.
  • a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.
  • the symbol ( ) denotes the point of attachment of a moiety to the remainder of the molecule.
  • a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as being “absent,” the named atom is replaced by a direct bond.
  • Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms.
  • Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • the term “congener” refers to one of two or more substances related to each other by origin, structure, or function.
  • enantiomer refers to one of a pair of molecular entities which are mirror images of each other and non-superposable.
  • stereoisomer refers to an isomer that possess identical constitution, but which differ in the arrangement of their atoms in space.
  • racemate refers to an equimolar mixture of a pair of enantiomers. It does not exhibit optical activity. The chemical name or formula of a racemate is distinguished from those of the enantiomers by the prefix ( ⁇ )- or rac- (or racem-) or by the symbols RS and SR.
  • diastereoisomerism refers to stereoisomerism other than enantiomerism.
  • Diastereoisomers or diastereomers are stereoisomers not related as mirror images. Diastereoisomers are characterized by differences in physical properties, and by some differences in chemical behavior towards achiral as well as chiral reagents. It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • the term “about,” when referring to a value can be meant to encompass variations of, in some embodiments, ⁇ 100% in some embodiments ⁇ 50%, in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.
  • the term “about” when used in connection with one or more numbers or numerical ranges should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth.
  • NAAG pre-synaptic metabotropic glutamate 3 receptors
  • GCPII inhibitors and various agonists/antagonists of ionotropic and metabotropic glutamate receptors have demonstrated analgesic activity in diverse rodent models of both acute and chronic pain, including models of thermal hyperalgesia, mechanical allodynia, neuropathic pain, and inflammatory pain.
  • iGluR/mGluR various agonists/antagonists of ionotropic and metabotropic glutamate receptors
  • Visceral Pain is a large unmet medical need
  • non-addictive analgesic agents to treat visceral pain, defined as the pain emanating from internal organs, including, but not limited to, the stomach, bladder, pancreas, abdomen and rectum.
  • GI National Gastrointestinal
  • PROM patient-reported outcomes measures
  • IBD Inflammatory Bowel Disease
  • IBS Irritable Bowel Syndrome
  • IBD3540 and JHU 241 attenuate visceral pain in the following chronic visceral hypersensitivity (CVH) models: (1) surgically induced TNBS-CVH of adult rats (IBD3540 and JHU 241); (2) enema induced AA-CVH of juvenile mice (IBD3540 only); and (3) enema induced TNBS- CVH of adult mice (IBD3540 only).
  • IBD3540 and JHU 241 were first evaluated in a rat model of CVH, in which a surgical administration of caustic chemical 2,4,6-trinitrobenzene sulfonic acid (TNBS) in the proximal colon results in hypersensitization to balloon colorectal distension (CRD).
  • TNBS caustic chemical 2,4,6-trinitrobenzene sulfonic acid
  • gut-restricted GCPII inhibitor IBD3540 for analgesic activity in a second mechanistically distinct model of CVH, in which juvenile mice are sensitized with a single enema of diluted acetic acid as neonates precipitating visceral hyperresponsivity in adulthood.
  • gut restricted means that the drug or therapeutic agent stays in the gut with minimal exposure to the rest of the body when given orally, thereby targeting gastrointestinal GCPII while limiting systemic side effects.
  • FIG. 6 demonstrate potent analgesic efficacy of oral (S)-IBD3540 when administered for an acute, 7-day, period.
  • IBD3540 analgesic effect
  • (S)-IBD3540 was administered to adult mice via an intrarectal enema, as opposed to a surgical instillation in the proximal colon utilized in the rat TNBS model.
  • mice Following the TNBS enema the mice are maintained for 6-8 weeks allowing for colon recovery from TNBS-induced chemical injury/ulceration and measurement of visceral hyperalgesia in a post-inflammatory state.
  • PO (S)- IBD3540 head-to-head versus 300 mg/kg PO gabapentin. Again, we observed potent analgesic activity.
  • Both the 2.75 mg/kg and 27.5 mg/kg PO (S)-IBD3540 were significantly analgesic and the magnitude of analgesic efficacy was equivalent to high-dose gabapentin (FIG. 8).
  • (S)-IBD3540 attenuated hypersensitivity to baseline levels.
  • TNBS 2,4,6-trinitrobenzene sulfonic acid
  • colonic sensitivity was assessed by measuring the intracolonic pressure required to induce a pain behavioral response.
  • a 5-cm balloon was inserted through the anus and gently advanced to a 10 cm intracolonic distance. Following a 30-minute acclimation period, the balloon was gradually inflated in 5 mmHg steps every 30 sec, from 5 to a maximum of 75 mmHg.
  • the pressure at which pain behavior was first elicited was recorded; pain behaviors were defined as elevation of the hind part of the animal body (lordosis) with clearly visible abdominal contraction (abdominal cramping). Behavioral responses were assessed by trained investigators blinded to treatment group.
  • mice Mouse chronic visceral hypersensitivity (CVH) models Neonatal C57BL/6 mice (7-10 days old), both genders, received a single intrarectal enema of vehicle or dilute acetic acid (AA) (0.5% AA, 50 ⁇ L) administered to awake mice via lubricated Hamilton syringe. In adulthood (6-8 months of age), mice underwent a brief surgical procedure to implant electrodes in the right abdominal musculature for measurement of abdominal electromyography. Following a 72-h surgical recovery period, mice were randomized to treatment groups, and were then treated once daily for 7 days (acute) or 28 days (chronic) with vehicle, gabapentin, or IBD3540 at doses indicated in figure legends.
  • CVH Mouse chronic visceral hypersensitivity
  • TNBS 2,4,6-trinitrobenzene sulfonic acid
  • mice Post-sensitization, body weight was monitored daily and those exhibiting characteristic body weight loss (>5% for ⁇ 2 consecutive days) were included in experimental cohorts.
  • experimental mice underwent surgery to implant electrodes in the right abdominal musculature for measurement of abdominal electromyography. Following a 72h surgical recovery period, mice were randomized to treatment groups, and were then treated once daily for 7 days with vehicle, gabapentin, or IBD3540 at concentrations indicated in figure legends. 60 minutes after the final dose visceromotor response to graded colorectal distension was measured using defined pressures of 15, 30, 50 and 70 mmHg. All measurements were made in duplicate.
  • NAALADase N-acetylated-alpha-linked-acidic dipeptidase
  • Synapse 2001 41, 22-28. Jackson P.F., Slusher B.S., Design of NAALADase inhibitors: a novel neuroprotective strategy.

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Abstract

GCPII inhibitors and their use in treating visceral pain, including abdominal pain, are disclosed.

Description

INHIBITION OF GCPII IN THE ENTERIC NERVOUS SYSTEM AS A NOVEL THERAPEUTIC FOR VISCERAL PAIN CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63/603,350 filed on November 28, 2023, which is incorporated herein by reference in its entirety. BACKGROUND GCPII catalyzes the hydrolysis of the abundant neuropeptide N- acetylaspartylglutamate (NAAG) to glutamate. The clinical relevance of this pathway is evidenced by the widespread interest in developing analgesic drugs specifically targeting NAAG/glutamate conversion or attenuating excess glutamate signaling. Indeed, GCPII inhibitors and various agonists/antagonists of ionotropic and metabotropic glutamate receptors (iGluR/mGluR) have demonstrated analgesic activity in diverse rodent models of both acute and chronic pain, including models of neuropathic pain, cancer pain, burn pain, incisional pain, diabetic neuropathy-induced pain, and inflammatory pain. The ability of GCPII inhibitors to treat visceral pain, however, has not been investigated. SUMMARY In some aspects, the presently disclosed subject matter provides a method for treating visceral pain, the method comprising administering to a subject in need of treatment thereof, a GCPII inhibitor. Representative GCPII inhibitors include, but are not limited to, bile acid conjugates with 2-(phosphonomethyl) pentanedioic acid (2-PMPA), hydroxamate-based GCPII inhibitors and prodrugs thereof, phosphonate-based GCPII inhibitors and prodrugs thereof, L-DOPA, D-DOPA, Caffeic acid, and prodrugs thereof, phosphinate-based GCPII inhibitors, phosphoramidate-based GCPII inhibitors, thiol-based GCPII inhibitors, urea- based GCPII inhibitors, dendrimer conjugates of 2-PMPA, 2-MPPA, and other GCPII inhibitors. In certain aspects, the visceral pain includes abdominal pain. In certain aspects, the GCPII inhibitor is administered orally. Certain aspects of the presently disclosed subject matter having been stated hereinabove, which are addressed in whole or in part by the presently disclosed subject matter, other aspects will become evident as the description proceeds when taken in connection with the accompanying Examples and Figures as best described herein below. BRIEF DESCRIPTION OF THE FIGURES The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Having thus described the presently disclosed subject matter in general terms, reference will now be made to the accompanying Figures, which are not necessarily drawn to scale, and wherein: FIG. 1 is a scheme illustrating that GCPII inhibition blocks excess glutamate transmission through a dual mechanism of increasing NAAG (mGluR3 agonism) and decreasing glutamate; FIG. 2A, FIG. 2B, and FIG. 2C demonstrate that IBD3540 is a potent GCPII inhibitor that is gut-restricted in normal and colitic mice. FIG. 2A shows the chemical structure of IBD3540; a construct containing the GCPII inhibitor 2-(phosphonomethyl)- pentanedioic acid (2-PMPA) conjugated to deoxycholic acid (DCA) via an ester linkage at the C24 position; (FIG. 2B) IBD3540 is a potent, nanomolar, inhibitor of human GCPII (IC50 = 4 ±0.1 nM; FIG.2C shows pharmacokinetic profiles of parent IBD3540 and metabolite 2-PMPA in colon and plasma following oral administration of 100 mg/kg eq. IBD3540 to healthy (blue) or colitic (red) mice (n=3/timepoint). Both IBD3540 (left) and 2- PMPA (right) displayed colon-restricted delivery as evidenced by colon:plasma AUC ratios > 16 under all conditions; FIG. 3A and FIG. 3B show that JHU 241 is a potent GCPII inhibitor. FIG. 3A is the chemical structure of JHU 241, which includes a zinc-binding group (hydroxamic acid) bound to a side chain substituent (benzoate function) via a flexible linker (2-carboxybutyl moiety); FIG. 3B demonstrates that JHU 241 is a potent, nanomolar, inhibitor of human GCPII (IC50 = 40±0.3nM); FIG. 4 demonstrates that representative GCPII inhibitors, IBD3540 and JHU 241, are analgesic in rat 2,4,6-Trinitrobenzene sulfonic acid (TNBS)-induced chronic visceral hypersensitivity (CVH) model. Once daily IBD3540 (275 mg/kg PO) and JHU 241 (10 mg/kg PO) reduced visceral pain, as evidenced by normalized colorectal distension thresholds in rats surgically instilled with TNBS in the proximal colon on day 0 followed by balloon colorectal distension on day 7 at 60 minutes post-drug administration. (n=8/group; Mean ± SEM); FIG. 5 demonstrates that gut-restricted GCPII inhibitor IBD3540 is analgesic in mouse AA-CVH at doses as low as 2.75 mg/kg. One week of treatment with once daily IBD3540 (2.75 and 27.5 mg/kg PO) attenuated visceral pain in adult mice, who had been sensitized with acetic acid (AA-CVH) as neonates, while doses of (0.0275 and 0.275 mg/kg were below the minimum effective dose) . (n=5-6/group; 2-way ANOVA with Newman- Keuls post-hoc analysis, & p<0.001, * p< 0.05, **p<0.01, ***p<0.001, ****p<0.0001) FIG. 6 demonstrates that gut-restricted GCPII inhibitor IBD3540 has equal analgesic activity to high-dose gabapentin in AA-CVH. One week of treatment with once daily IBD3540 (27.5 mg/kg PO) attenuated visceral pain in adult mice, who had been sensitized with acetic acid (AA-CVH) as neonates, with equal efficacy when compared head-to-head versus gabapentin (300 mg/kg PO). (n=5-6/group, 2-way ANOVA with Newman-Keuls post-hoc analysis, & p<0.001, *p<0.05, **p<0.01); FIG. 7 demonstrates that repeated oral administration of (S)-IBD3540 retains analgesic efficacy in AA-CVH. As above, neonatal mice were sensitized with diluted acetic acid or saline followed by randomization to experimental groups at 4-6 months of age. Mice were treated with oral (S)-IBD3540 (10 mg/kg 2-PMPA eq.), or vehicle once daily for 28 days. 60 minutes after the final dose VMR to CRD was measured (n=5-6/group; 2-way ANOVA with Newman-Keuls post-hoc analysis, & p<0.001, * p< 0.05, **p<0.01); and FIG. 8 demonstrates that gut-restricted GCPII inhibitor IBD3540 displays potent analgesic activity in mouse TNBS-CVH. One week of treatment with once daily IBD3540 (2.75 or 27.5 mg/kg PO) significantly attenuated visceral pain in mice, who had been sensitized with enema TNBS followed by a 5 week recovery period, with comparable efficacy gabapentin (300 mg/kg PO). (n=5-6/group; 2-way ANOVA with Newman-Keuls post-hoc analysis, & p<0.001, * p< 0.05, **p<0.01). DETAILED DESCRIPTION The presently disclosed subject matter now will be described more fully hereinafter with reference to the accompanying Figures, in which some, but not all embodiments of the inventions are shown. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated Figures. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Visceral pain describes pain emanating from the internal thoracic, pelvic, or abdominal organs. Unlike somatic pain, which occurs in tissues, such as the muscles, skin, or joints, visceral pain is associated with the viscera, which encompasses the organs of the abdominal cavity, including the sex organs, spleen, and parts of the digestive system. Visceral structures are highly sensitive to distension (stretch), ischemia, and inflammation. Visceral pain can originate from an ongoing injury to the internal organs or the tissues that support them or can arise as secondary to a disease, disorder, or condition of an internal organ. Visceral pain is often vague and can be described as a deep ache, pressure, gnawing, twisting, colicky, or dull. Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus, such as organ distension. These characteristics make visceral pain more difficult to pinpoint and treat. Although visceral pain originates in the organs of the chest, abdomen, or pelvis it also may be felt it in other areas of the body. Visceral pain can be accompanied by other symptoms including, but not limited to, nausea, vomiting, sweating, a racing heart, and changes in other vital signs. Common causes of visceral pain include, but are not limited to, inflammation, menstrual cramps, swelling and stretching of the organs, blockage, particularly of the bowels or urethra, decreased blood flow and tumors, particularly when concentrated in the pelvis or abdomen. Visceral pain also can result from one or more conditions selected from a urogenital disorder, including conditions affecting the urinary tract and/or the genital tract, i.e., reproductive organs; a urologic disorder, including conditions affecting the urinary tract, i.e. kidneys, ureters, or bladder, such as bladder neoplasm, chronic urinary tract infection, interstitial cystitis, radiation cystitis, recurrent cystitis, recurrent urethritis, urolithiasis, uninhibited bladder contractions (detrusor-sphincter dyssynergia), urethral diverticulum, chronic urethral syndrome, urethral carbuncle, and urethral stricture; a genital disorder, including conditions affecting the genital tract, such as testicular torsion, prostatitis, and Peyronie’s disease. Visceral pain is a prevalent, debilitating condition with limited treatment options and thus remains a major clinical problem. Although some visceral pain disorders are not life- threatening, they still contribute significantly to a large segment of healthcare resource consumption and have a considerable negative impact on lives with psychological distress and disturbance of work, sleep, and sexual dysfunction. Accordingly, in some embodiments, the presently disclosed subject matter provides GCPII inhibitors for use in treating visceral pain, including abdominal pain. Although glutamatergic signaling pathways have received lesser characterization in the enteric nervous system (ENS), all subtypes of mGluRs and iGluRs present in the CNS/PNS have been identified in mammalian gastrointestinal tissues. Recent studies also have shown that glutamate secreted by colon epithelial EECs can activate vagal afferents, suggesting that epithelial-derived glutamate may be a key player in visceral pain signaling. Accordingly, it was thought that inhibiting GCPII with small molecule inhibitors might attenuate visceral pain, including abdominal pain. The presently disclosed subject matter demonstrates that structurally distinct classes of GCPII inhibitors are robustly analgesic in preclinical visceral pain models. GCPII inhibitors generally fall into the following representative classes including, but not limited to, phosphonates, including bile acid conjugates of phosphonates, such as 2- PMPA, phosphinates, phosphoramidates, thiols, hydroxamates, and ureas:
Figure imgf000007_0001
(hydroxamates); and (ureas), wherein R1, R2, R3, R’3, and R4 are substituent groups as defined herein. See, for example, Vornov et al., 2020; Pastorino et al., 2020; Gourni and Henriksen, 2017; Bařinka et al., 2012. Known GCPII inhibitors representative of these general classes include 2- (phosphonomethyl) pentanedioic acid (2-PMPA) (phosphonates), 2-(3- mercaptopropyl)pentanedioic acid (2-MPPA) (thiols), 2-(2-(hydroxyamino)-2- oxoethyl)pentanedioic acid (JHU 241) (hydroxamates), see also Rais et al., 2017, for other hydroxamate-based glutamate GCPII inhibitors, including, 4-carboxy-alpha-[3- (hydroxyamino)-3-oxopropyl]-benzenepropanoic acid, and N-[N-[(S)]-1,3-dicarboxypropyl] carbamoyl]-L-leucine (ZJ-43) (ureas):
Figure imgf000007_0002
Other phosphonate-based GCPII inhibitors include GPI-5232, Jackson and Slusher, 2001, and VA-033, Ding et al., 2004: E
Figure imgf000008_0001
xamples of these classes of GCPII inhibitors are presented herein below. A. Bile Acid Conjugates with 2-(phosphonomethyl) pentanedioic acid (2-PMPA) In some embodiments, the presently disclosed GCPII inhibitors can be formed by conjugating the potent GCPII inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) to a bile acid. The chemical formula of 2-PMPA is provided immediately herein below: (2-PMPA). Bile acids, which are abundant endogenously, were selected as the conjugate as they also are reported to have direct immunomodulatory effects in a variety of inflammatory models, Sipka and Bruckner, 2014; Calmus and Poupon, 2014; Ho and Steinman, 2016, including protection in IBD models. Laukens, et al., 2014. Bile acids have the following general chemical structure:
Figure imgf000008_0002
wherein: R'1 and R'2 are each independently H or -OH; R'3 is -OH; R'4 is selected from the group consisting of -OH, -NHCH2COOH, and -NHCH2CH2SO3H; and salts thereof. Representative bile acids include, but are not limited to, cholic acid, glycocholic acid, deoxycholic acid, lithocholic acid, glycodeoxycholic acid, chenodeoxycholic acid (also referred to as chenocholic acid), glycochenodeoxycholic acid, ursodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, and derivatives thereof, the structures of which are provided immediately herein below in Table 1. Table 1. Representative Bile Acids
Figure imgf000009_0001
Table 1. Representative Bile Acids
Figure imgf000010_0001
Table 1. Representative Bile Acids ovides a conjuga
Figure imgf000011_0002
te of 2-(phosphonomethyl) pentanedioic acid (2-PMPA), or a derivative thereof, and a bile acid, or derivative thereof. Representative bile acid conjugates of 2-PMPA are disclosed in International PCT Patent Application No. WO2021155167 for Bile Acid-GCPII Inhibitor Conjugates to Treat Inflammatory Diseases, to Slusher et al., published August 5, 2021, which is incorporated by reference in its entirety. In some embodiments, the conjugate comprises a compound of formula (I): wherein:
Figure imgf000011_0001
R1 and R2 are each independently H or -OH; R3 is OH; and R4 is selected from the group consisting of -NH-X1, -COO-X1, -C(=O)-NH-CH2- C(=O)-O-X1, and -C(=O)-NH-CH2-CH2-S(=O)2-O-X1,wherein X1 is selected from the group consisting of -(C=O)-(CH2)m-P(=O)(OH)-X2, -(C=O)-(CH2)m-CH(COOH)-CH2-P(=O)(OH)- X2, -CH2-O-(C=O)-(CH2)m-P(=O)(OH)-X2, -CH2-O-C(=O)-(CH2)m-CH(COOH)-CH2- P(=O)(OH)-X2, -CH2-O-C(=O)-(CH2)m-CH(COOH)-NH-(C=O)-NH-CH(COOH)-CH2- CH(CH3)2, -CH2-O-C(=O)-Ar-CH2-CH(COOH)-(CH2)m-C(=O)-NH-OH, -CH2-O-C(=O)- (CH2)m-X3, -CH2-O-C(=O)-Ar-CH2-X3, and a protecting group, wherein X2 is selected from the group consisting of -OH, -CH2-CH(COOH)-(CH2)p-C(=O)-OH, and a protecting group, Ar is arylene, and X3 is 2-oxotetrahydro-2H-thiopyran-3-yl, and each m and p is independently selected from the group consisting of 1, 2, 3, and 4; or R3 is selected from the group consisting of -O-C(=O)-O-CH2-O-C(=O)-(CH2)n- CH(COOH)-CH2-P(=O)(OH)2, and -O-C(=O)-CH2-CH2-P(=O)(OH)-CH2-CH(COOH)- (CH2)n-C(=O)-OH, wherein each n is independently an integer selected from the group consisting of 1, 2, 3, and 4; and R4 is selected from the group consisting of -NH2, -COOH, -C(=O)-NH-CH2-C(=O)- OH, and -C(=O)-NH-CH2-CH2-S(=O)2-OH; and pharmaceutically acceptable salts thereof. In some embodiments, R1 and R2 are both H. In some embodiments, R1 is H and R2 is OH. In some embodiments, R1 is OH and R2 is H. In some embodiments, R1 and R2 are both OH. In some embodiments, R3 is OH and R4 is selected from the group consisting of - NH-X1, -COO-X1, -C(=O)-NH-CH2-C(=O)-O-X1, and -C(=O)-NH-CH2-CH2-S(=O)2-O-X1, wherein X1 is selected from the group consisting of -(C=O)-CH2-CH2-P(=O)(OH)-X2, - (C=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O-(C=O)-CH2-CH2-P(=O)(OH)- X2, -CH2-O-C(=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O-C(=O)-CH2-CH2- CH(COOH)-NH-(C=O)-NH-CH(COOH)-CH2-CH(CH3)2, -CH2-O-C(=O)-Ar-CH2- CH(COOH)-CH2CH2-C(=O)-NH-OH, -CH2-O-C(=O)-CH2-CH2-X3, -CH2-O-C(=O)-Ar- CH2-X3, and a protecting group, wherein X2 is selected from the group consisting of -OH, - CH2-CH(COOH)-CH2-CH2-CH(=O)-OH, and a protecting group, Ar is phenyl, and X3 is 2- oxotetrahydro-2H-thiopyran-3-yl. In some embodiments, R1 is OH, R2 is H, R3 is OH, and R4 is COO-X1, wherein X1 is -CH2-O-C(=O)-(CH2)m-CH(COOH)-CH2-P(=O)(OH)-X2. In some embodiments, R1 is H and R2 is OH or R1 is OH and R2 is H, R3 is OH, and R4 is -NH-X1, wherein X1 is -(C=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)-X2. In some embodiments, the compound of formula (I) is selected from the group consisting of:
Figure imgf000013_0001
Figure imgf000014_0001
and . In some embodiments, R3 is selected from the group consisting of -O-C(=O)-O-CH2- O-C(=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)2, and -O-C(=O)-CH2-CH2-P(=O)(OH)- CH2-CH(COOH)-CH2-CH2-C(=O)-OH, and R4 is selected from the group consisting of - NH2, -COOH, -C(=O)-NH-CH2-C(=O)-OH, and -C(=O)-NH-CH2-CH2-S(=O)2-OH. In such embodiments, the compound of formula (I) is selected from the group consisting of:
Figure imgf000015_0003
. B. Hydroxamate-based GCPII Inhibitors and Prodrugs Thereof Hydroxamate-based GCPII inhibitors include 2-(2-(hydroxyamino)-2- oxoethyl)pentanedioic acid (JHU 241) and 4-carboxy-alpha-[3-(hydroxyamino)-3- oxopropyl]-benzenepropanoic acid. See Stoermer et al., 2003; Novakova et al., 2016; and Rais et al., 2017, for other hydroxamate-based glutamate GCPII inhibitors. In some embodiments, the GCPII inhibitor is a hydroxamate-based GCPII inhibitor of formula (IIa):
Figure imgf000015_0001
wherein n is an integer selected from 0, 1, 2, and 3. In particular embodiments, the hydroxamate-based GCPII inhibitor comprises:
Figure imgf000015_0002
Representative prodrugs of hydroxamate-based GCPII inhibitors are disclosed in International PCT Patent Application Publication No. WO2018094334 for Prodrugs of Hydroxamate-Based GCPII Inhibitors, to Slusher et al., published May 24, 2018, which is incorporated herein by reference in its entirety, in particular, page 6, line 31, through page 17, line 1; U.S. Patent No. 11,059,775 for Prodrug compositions and utility of hydroxamate- based GCPII inhibitors, to Slusher et al., issued July 13, 2021; and U.S. Patent Application Publication No. US 2021-0355079 A1 for Prodrug compositions and utility of hydroxamate- based GCPII inhibitors, to Slusher et al., published November 18, 2021, each of which is incorporated herein by reference in its entirety. In some embodiments, the presently disclosed subject matter provides prodrugs of hydroxamate-based GCPII inhibitors compound of formula (IIb):
Figure imgf000016_0001
wherein: R1 is selected from the group consisting of -C(=O)-O-R4 and -Ar-C(=O)-O-R4; R2 is selected from the group consisting of substituted and unsubstituted C1-C6 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C12 aryl, substituted and unsubstituted C6-C12 heteroaryl, -(CR5R6)n-R7, -C(=O)-O-R7, -C(=O)-R7,- C(=O)-NR7R8, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7; R3 is selected from the group consisting of H, substituted and unsubstituted C1-C6 alkyl, substituted and unsubstituted C3-C12 cycloalkyl, substituted and unsubstituted C6-C12 aryl, substituted and unsubstituted C5-C12 heteroaryl; R4 is selected from the group consisting of H, substituted and unsubstituted C1-C6 alkyl, substituted and unsubstituted C3-C12 cycloalkyl, substituted and unsubstituted C6-C12 aryl, substituted and unsubstituted C5-C12 heteroaryl, -(CR5R6)n-O- C(=O)-O-R9, and -(CR5R6)n-Ar-O-C(=O)-R9; each R5 and R6 is independently selected from the group consisting of H, C1-C10 alkyl, and C6-C12 aralkyl; R7 is selected from the group consisting of H, and substituted and unsubstituted C1-C10 alkyl, substituted and unsubstituted C1-C10 heteroalkyl, substituted and unsubstituted C3-C16 cycloalkyl, substituted and unsubstituted C3-C12 cycloheteroalkyl, substituted and unsubstituted C3-C12 cycloheteroalkenyl, substituted and unsubstituted C6-C12 aryl, substituted and unsubstituted C6-C12 heteroaryl, and substituted and unsubstituted C6-C12 aralkyl; R8 is selected from the group consisting of H, and substituted and unsubstituted C1-C6 alkyl; R9 is selected from the group consisting of H, and substituted and unsubstituted C1-C6 alkyl; n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; Ar is selected from the group consisting of substituted and unsubstituted C6-C12 aryl, and substituted and unsubstituted C6-C12 heteroaryl; and stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments, the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000017_0001
wherein R2, R3, and R4, are as defined hereinabove; and stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments, R2 is as defined hereinabove; R3 is selected from the group consisting of H and substituted and unsubstituted C1-C6 alkyl; R4 is selected from the group consisting of H, substituted and unsubstituted C1-C6 alkyl, -(CR5R6)n-Ar-O-C(=O)- R9, and - (CR5R6)n-O-C(=O)-O-R9; n is 1; R5 andR6 are H; Ar is phenyl; R9 is selected from the group consisting of substituted C1-C3 alkyl, and unsubstituted C1-C3 alkyl; and stereoisomers and pharmaceutically acceptable salts thereof. In some embodiments R2 is -(CR5R6)n-Ar-O-C(=O)-R7, n is 1, Ar is phenyl, and R7 is substituted or unsubstituted C1-C6 alkyl. In particular embodiments, the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000018_0001
In other embodiments, R2 is -(CR5R6)n-R7 , n is 1, and R7 is substituted C3-C12 cycloheteroalkenyl. In particular embodiments, the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000019_0001
. In some embodiments R2 is -C(=O)-R7, and R7 is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, unsubstituted C6-C12 aryl, or unsubstituted C6-C12 aralkyl. In particular embodiments, the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000019_0002
Figure imgf000020_0001
In some embodiments, R2 is -C(=O)-O-R7, and R7 is unsubstituted C1-C6 alkyl. In particular embodiments, the compound of formula (IIb) is:
Figure imgf000020_0002
In some embodiments, R2 is -C(=O)-NR7R8, R7 is substituted C1-C6 alkyl, or substituted C3-C16 cycloalkyl, and R8 is H. In particular embodiments, the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000021_0001
; and . C. Phosphonate-based GCPII Inhibitors, including 2-PMPA, and Prodrugs Thereof In some embodiments, the GCPII inhibitor is 2-PMPA or a prodrug thereof. Representative prodrugs of 2-PMPA are disclosed in International PCT Patent Application Publication No. WO2016022827 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., published February 11, 2016, which is incorporated by reference in its entirety, in particular page 9, line 19, through page 25, line 12. In some embodiments, the presently disclosed subject matter provides a compound of formula (IIIa) or formula (IIIb): wh
Figure imgf000021_0002
erein: each R1, R2, R3, and R4 is independently selected from the group consisting of H, alkyl, Ar, -( CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n-C(=O)-O-R7, -(CR5R6)n-O- C(=O)-O-R7,-(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7,- Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; wherein: n is an integer from 1 to 20; m is an integer from 1 to 20; each R3' and R4' are independently H or alkyl; each R5 and R6 is independently selected from the group consisting of H, alkyl, and alkylaryl; each R7 is independently straightchain or branched alkyl; Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; and R8 and R9 are each independently H or alkyl; and pharmaceutically acceptable salts thereof. In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000022_0001
In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of: , , and . In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000023_0001
In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000023_0003
In particular embodiments, the compound of formula (IIIa) is:
Figure imgf000023_0002
In particular embodiments, the compound of formula (IIIa) is: In particular emb
Figure imgf000024_0001
odiments, the compound of formula (IIIa) is:
Figure imgf000024_0002
In particular embodiments, the compound of formula (IIIa) is:
Figure imgf000024_0003
In particular embodiments, the compound of formula (IIIa) is:
Figure imgf000024_0004
In particular embodiments, the compound of formula (IIIa) is:
Figure imgf000024_0005
In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000025_0001
In particular embodiments, the compound of formula (IIIa) is: In partic
Figure imgf000025_0002
ular embodiments, the compound of formula (IIIa) is:
Figure imgf000025_0003
In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000025_0004
and . In particular embodiments, the compound of formula (IIIa) is:
Figure imgf000026_0004
. In particular embodiments, the compound of formula (IIIa) is In part
Figure imgf000026_0005
icular embodiments, the compound of formula (IIIa) is In
Figure imgf000026_0002
particular embodiments, the compound of formula (IIIa) is:
Figure imgf000026_0003
In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000026_0001
In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000027_0003
In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000027_0001
In particular embodiments, the compound of formula (IIIa) is:
Figure imgf000027_0002
In particular embodiments, the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000028_0001
, and . In particular embodiments, the compound of formula (IIIb) is:
Figure imgf000028_0002
In particular embodiments, the compound of formula (IIIb) is:
Figure imgf000028_0003
In certain embodiments: (a) each R1 is H; each R2 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4 is selected from the group consisting of -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, - (CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n- C(=O)-NR8R9; (b) each R1 is alkyl; each R2 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4 is selected from the group consisting of Ar, -(CR5R6)n-O-C(=O)-R7, - (CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n- O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and - (CR5R6)n-C(=O)-NR8R9; (c) each R1 is-(CR5R6)n-Ar; each R2 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4 is selected from the group consisting of Ar, -(CR5R6)n-O-C(=O)-R7, - (CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n- O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and - (CR5R6)n-C(=O)-NR8R9; or (d) each R1 is selected from Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, - (CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar- O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R2 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; wherein: each n is an integer from 1 to 20; each m is an integer from 1 to 20; each R5 and R6 is independently selected from the group consisting of H, alkyl, and alkylaryl; each R7 is independently straight chain or branched alkyl; each Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; each R8 and R9 are independently H or alkyl; and each R3' and R4' are independently H or alkyl; and pharmaceutically acceptable salts thereof. In some embodiments, the compound is a compound of formula (IIIa) and: R1 is H; R2 and R3 are each selected from the group consisting of H, -(CR5R6)n-O-R7, - (CR5R6)n-Ar-O-C(=O)-R7, -(CR5R6)n-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, and - (CR5R6)n-O-C(=O)-O-R7; and R4 is selected from the group consisting of -(CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)- R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof. In some embodiments, the compound is a compound of formula (IIIa) and: R1 is alkyl; R2 and R3 are each independently selected from the group consisting of H, alkyl, - (CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-O- C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; and R4 is selected from the group consisting of -(CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)- R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof. In some embodiments, the compound is a compound of formula (IIIa) and: R1 is selected from -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; and R2 R3, and R4 are each independently selected from H, Ar, -(CR5R6)n-O-C(=O)-R7, and -(CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof. In some embodiments, the compound is a compound of formula (IIIa) and: one of R1, R2, R3, or R4 is H and the other three are each independently selected from the group consisting of: -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; wherein R5 and R6 are each independently selected from the group consisting of H, C1-8 straight-chain alkyl, and C1-8 branched-chain alkyl; R7 is C1-8 straight-chain alkyl, and C1-8 branched-chain alkyl; and pharmaceutically acceptable salts thereof. In some embodiments, the compound is a compound of formula (IIIa) and: R2 is H; and R1, R3, and R4 are each independently selected from the group consisting of: -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; wherein R5 and R6 are each independently selected from the group consisting of H, C1-8 straight-chain alkyl, and C1-8 branched-chain alkyl; R7 is C1-8 straight-chain alkyl or C1-8 branched-chain alkyl; and pharmaceutically acceptable salts thereof. In some embodiments, R5 and R6 are each H. Representative embodiments of 2-PMPA prodrugs are disclosed in: U.S. Patent No. 10,544,176 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., issued January 28, 2020; U.S. Patent No. 9,988,407 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., issued June 5, 2018; U.S. Patent Application Publication No. US 2020-0399298 A1 for Prodrugs of Prostate Specific Membrane Antigen (PSMA) Inhibitor, to Slusher et al., published December 24, 2020, each of which is incorporated herein by reference in its entirety. Other phosphonate-based GCPII inhibitors include GPI-5232, Jackson and Slusher, 2001, and VA-033, Ding et al., 2004:
Figure imgf000032_0001
D. L-DOPA, D-DOPA, Caffeic acid, and Prodrugs Thereof In some embodiments, the presently disclosed subject matter provides L-DOPA, D- DOPA, caffeic acid, and prodrugs thereof as GCPII inhibitors. Representative prodrugs of L- DOPA, D-DOPA, and caffeic acid are disclosed in International PCT Patent Application Publication No. WO2023064783 for DOPA and Caffeic Acid Analogs As Novel GCPII Inhibitors, to Rais et al., published April 20, 2023, which is incorporated herein by reference in its entirety. More particularly, the presently disclosed subject matter provides prodrugs of L- DOPA, D-DOPA, and caffeic acid as compounds of formula (IV): wherein:
Figure imgf000033_0001
indicates that the bond can be a single or a double bond; R1 is: -OR5, wherein R5 is selected from the group consisting of H, C1-C8 alkyl, and -O- (CH2)n-R6, wherein n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8 and R6 is substituted or unsubstituted aryl or heteroaryl; or -NR7R8, wherein R7 and R8 are each independently selected from the group consisting of H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C8 alkoxyl, unsubstituted or substituted aryl or heteroaryl, -(CH2)m-R9, wherein R9 is -OR10 or CHX2, wherein R10 is H or C1-C4 alkyl, and each X is halogen, and -(CH2)m-CH(NH2)(COOH), wherein each m is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; R2 is H or -NR11R12, whereinR11 and R12 are each independently selected from the group consisting of H, C1-C4 alkyl, and -C(=O)-R13, whereinR13 is C1-C4 alkyl or -C(NH2)-(CH2)p-R14, whereinR14 is C1-C4 alkyl or -NR15R16, wherein R15 and R16 are each H or C1-C4 alkyl, and p is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; R3 and R4 are each independently H or -C(=O)-R17, wherein R17 is C1-C8 alkyl or -(CH2)t-O-C(=O)-O-R18, wherein R18 is C1-C8 alkyl, and t is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; and stereoisomers and pharmaceutically acceptable salts thereof. In certain embodiments, R1 is -OR5, and R5 is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec- pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, and n-octyl. In certain embodiments, R1 is -OR5, and R5 is H or -O-(CH2)n-R6, wherein R6 is substituted or unsubstituted phenyl. In certain embodiments, R1 is -NR7R8, and R7 is H or C1-C4 alkyl and R8 is selected from the group consisting of H, C1-C4 alkyl, C3-C6 cycloalkyl, unsubstituted or substituted phenyl, -(CH2)m-R9, wherein R9 is -OR10 or CHX2, wherein R10 is H or C1-C4 alkyl, and each X is halogen, and -(CH2)m-CH(NH2)(COOH), wherein each m is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8. In certain embodiments, R2 is -NR11R12, wherein R11 is H and R12 is H or -C(=O)- R13, wherein R13 is C1-C4 alkyl or -C(NH2)-(CH2)p-R14, wherein R14 is C1-C4 alkyl or -NR15R16, wherein R15 and R16 are each H or C1-C4 alkyl, and p is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8. In certain embodiments, R3 and R4 are each H. In certain embodiments, if R1 is -OR5, then R5 cannot be H. In certain embodiments, if R1 is -OR5, then R3, R4, and R5 cannot all be H. In certain embodiments, R3 and R4 are each independently selected from the group consisting of -C(=O)-CH3, -C(=O)-C(CH3)3, and -CH2-O-C(=O)-O-CH(CH3)2. In particular embodiments, the compound of formula (IV) is selected from the group consisting of:
Figure imgf000034_0001
Figure imgf000035_0001
; and . E. Phosphinate-based GCPII Inhibitors Representative phosphinate-based GCPII inhibitors include, but are not limited to: 2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[((2-phenylethyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[((3-phenylpropyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[((3-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[((2-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(4-phenylbutyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(aminomethyl)hydroxyphosphinyl]methyl]pentanedioic acid; 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid; 2-(phosphonomethyl)pentanedioic acid; N-[methylhydroxyphosphinyl]glutamic acid; N-[ethylhydroxyphosphinyl]glutamic acid; N-[propylhydroxyphosphinyl]glutamic acid; N-[butylhydroxyphosphinyl]glutamic acid; N-[phenylhydroxyphosphinyl]glutamic acid; and N-[(phenylmethyl)hydroxyphosphinyl]glutamic acid. See U.S. Patent No. 11,167,049, for Organ protection in PSMA-targeted radionuclide therapy of prostate cancer, to Babich et al., issued Nov. 9, 2021, which is incorporated herein by reference in its entirety. F. Phosphoramidate-based GCPII Inhibitors Phosphoramidate-based GCPII inhibitors include compounds of formula (V):
Figure imgf000036_0001
Representative phosphoramidate-based GCPII inhibitors are disclosed in Ferraris et al., 2012, and include compounds of formula (V’):
Figure imgf000036_0002
wherein R is H or C1-C4 alkyl, and R’ is benzyl; or a compound of formula (V”):
Figure imgf000037_0001
wherein R is selected from H, 4-fluorobenzoyl, and 6-(fluorescein-5-carboxamido)hexanoyl. G. Thiol-based GCPII Inhibitors Representative thiol-based GCPII inhibitors include 3-(2-mercaptoethyl)biphenyl- 2,3-dicarboxylic acid (E2072) and GPI-5693: See
Figure imgf000037_0002
Wozniak et al., 2012b; Slusher et al., 2001. Other thiol-based are provided in Bařinka et al., 2012, and International Patent Application No. WO2002057222 for Thiol-Based NAALADASE Inhibitors, to Tsukamoto et al., published July 25, 2002, which is incorporated herein by reference in its entirety. H. Urea-based GCPII Inhibitors Urea-based GCPII inhibitors include MIP-1555, MIP-1519, MIP-1545, MIP-1427, MIP-1428, MIP-1379, MIP-1072, MIP-1095, MIP-1558, MIP-1405, and MIP-1404. See U.S. Patent No. 11,167,049, for Organ protection in PSMA-targeted radionuclide therapy of prostate cancer, to Babich et al., issued Nov. 9, 2021, which is incorporated herein by reference in its entirety. Other urea-based GCPII inhibitors include PSMA I&T, Weineisen et al., 2015, PSMA-617, Benešová et al., 2015, PSMA-11, Eder et al., 2012, DCIBzL, Chen et al., 2008, 18F-DCFPyl, Chen et al., 2011, ZJ 38, GCPII-IN-1, and JB-352, Knedlík et al., 2017:
Figure imgf000038_0001
I. Dendrimer Conjugates of 2-PMPA, 2-MPPA, and other GCPII Inhibitors In some embodiments, the presently disclosed subject matter provides dendrimer conjugates of 2-PMPA, 2-MPPA, and other GCPII inhibitors and their use treating visceral pain. In some embodiments, the dendrimers are in the form of dendrimer nanoparticles comprising poly(amidoamine) (PAMAM) hydroxyl-terminated dendrimers covalently linked, for example to 2-PMPA, 2-MPPA, or another GCPII inhibitor. Representative dendrimer compositions suitable for use with the presently disclosed methods are disclosed in International PCT Patent Application Publication No. WO2016025745 for Dendrimer Compositions and use in Treatment of Neurological and CNS Disorders, to Rangaramanujam et al., published February 18, 2016, which is incorporated herein in its entirety. In particular embodiments, the dendrimer nanoparticles include one or more ethylene diamine-core PAMAM hydroxyl-terminated generation-4 through generation-10 (e.g., ≥G4- OH) dendrimers covalently linked to 2-PMPA. As used herein, the term “dendrimer” includes, but is not limited to, a molecular architecture having an interior core, interior layers (or “generations”) of repeating units regularly attached to the interior core, and an exterior surface of terminal groups attached to the outermost generation. Dendrimers suitable for use with the presently disclosed methods include, but are not limited to, polyamidoamine (PAMAM), polypropyiamine (POPAM), poly(propylene imine) (PPI), polyethylenimine, polylysine, polyester, iptycene, aliphatic poly(ether), and/or aromatic polyether dendrimers. Each dendrimer of the dendrimer complex may be of similar or different chemical nature than the other dendrimers (e.g., the first dendrimer may include a PAMAM dendrimer, while the second dendrimer may comprise a POPAM dendrimer). In some embodiments, the first or second dendrimer may further include an additional agent. In some embodiments, a multiarm PEG polymer can include a polyethylene glycol having at least two branches bearing sulfhydryl or thiopyridine terminal groups; however, embodiments disclosed herein are not limited to this class and PEG polymers hearing other terminal groups, such as succinimidyl or maleimide terminal groups, can be used. In particular embodiments, PEG polymers in the molecular weight 10 kDa to 80 kDa can be used. In certain embodiments, the dendrimer complex can include multiple dendrimers. For example, the dendrimer complex can include a third dendrimer; wherein the third- dendrimer is complexed with at least one other dendrimer. Further, a third agent can be complexed with the third dendrimer. In another embodiment, the first and second dendrimers are each complexed to a third dendrimer, wherein the first and second dendrimers are PAMAM dendrimers and the third dendrimer is a POPAM dendrimer. Additional dendrimers also can be incorporated. When multiple dendrimers are used, multiple agents also can be incorporated. This characteristic is not limited by the number of dendrimers complexed to one another. As used herein, the term “PAMAM dendrimer” refers to a poly(amidoamine) dendrimer, which may contain different cores, with amidoamine building blocks. The method for making them is known to those of skill In the art and generally, involves a two- step iterative reaction sequence that produces concentric shells (i.e., “generations”) of dendritic β-alanine units around a central interior core. This PAMAM core-shell architecture grows linearly in diameter as a function of added shells (generations). Meanwhile, the surface groups amplify exponentially at each generation according to dendritic-branching mathematics. Such dendrimers are available in generations G0 - G10 with 5 different core types and 10 functional surface groups. In certain embodiments, the PAMAM dendrimers can have carboxylic, amine and hydroxyl terminal groups and can be any generation of dendrimers including, but not limited to, generation 1 PAMAM dendrimers, generation 2 ΡΑΜAΜ dendrimers, generation 3 PAMAM dendrimers, generation 4 PAMAM dendrimers, generation 5 PAMAM dendrimers, generation 6 PAMAM dendrimers, generation 7 PAMAM dendrimers, generation 8 PAMAM dendrimers, generation 9 PAMAM dendrimers, or generation 10 PAMAM dendrimers. In particular embodiments, the PAMAM dendrimers can be generation 4 dendrimers, or more, with hydroxyl groups attached to their functional surface groups. Representative dendrimers suitable for use with the presently disclosed methods are disclosed in International PCT Patent Application Publication No. WO2009/046446 for Dendrimers for Sustained Release of Compounds, to Kannan et al., published April 9, 2009, which is incorporated herein by reference in its entirety. Dendrimer complexes can be formed by covalently bonding or otherwise attaching, e.g., via intermolecularly dispersion or encapsulation, a therapeutically active agent, e.g., 2- PMPA, to a dendrimer or multiarm PEG. The attachment can occur via an appropriate spacer that provides a disulfide bridge between the agent and the dendrimer. The dendrimer complexes are capable of rapid release of the agent in vivo by thiol exchange reactions, under the reduced conditions found in a body. The term “spacers” as used herein is intended to include compositions used for linking a therapeutically active agent to the dendrimer. The spacer can be either a single chemical entity or two or more chemical entities linked together to bridge the polymer and the therapeutic agent or imaging agent. The spacers can include any small chemical entity, peptide or polymers having sulfhydryl, thiopyridine, succinimidyl, maleimide, vinylsulfone, and carbonate terminal groups. In certain embodiments, the spacer can comprise thiopyridine terminated compounds including, but not limited to, dithiodipyridine, N-succinimidyl 3-(2-pyridyldithio)- propionate (SPDP), succinimidyl 6-(3-[2-pyridyldithio]-propionamido)hexanoate LC-SPDP, or Sulfo-LC-SPDP. The spacer also can include peptides wherein the peptides are linear or cyclic having sulfhydryl groups, such as glutathione, homocysteine, cysteine and its derivatives, arg-gly-asp-cys (RGDC), cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)), cyclo(Arg-Gly-Asp-D-Tyr-Cys), cyelo(Arg-Ala-Asp-d-Tyr-Cys). The spacer can be a mercapto acid derivative such as 3-mercapto propionic acid, mercapto acetic acid, 4- mercapto butyric acid, thiolan-2-one, 6-mercaptohexanoic acid, 5-mercapto valeric acid and other mercapto derivatives such as 2-mercaptoethanol and 2-mercaptoethylamine. The spacer can be thiosalicyclic acid and its derivatives including (4-succinimidyloxycarbonyl- methyl-α-2-pyridylthio)toluene and (3-[2-pyridithio]propionyl hydrazide. The spacer can have maleimide terminal groups wherein the spacer comprises polymer or small chemical entity, such as bis-maleimido diethylene glycol and bis-maleimido triethylene glycol, bismaleimidoethane, bismaleimidohexane. The spacer can comprise a vinylsulfone, such as 1,6-hexane-bis-vinylsulfone. The spacer can comprise thioglycosides, such as thioglucose. The spacer can be a reduced protein, such as bovine serum albumin and human serum albumin, or any thiol terminated compound capable of forming disulfide bonds. The spacer can include polyethylene glycol having maleimide, succinimidyl and thiol terminal groups. J. Other GCPII Inhibitors Other representative GCPII inhibitors include quisqualate and β-citryl-L-glutamate:
Figure imgf000041_0001
In some embodiments, the GCPII inhibitor includes: (S)-2-((N-((S)-1,2-dicarboxyethyl)sulfamoyl)amino)pentanedioic acid:
Figure imgf000041_0002
(S)-2-((((S)-5-(4-bromo-2-fluorobenzamido)-1-carboxypentyl)carbamoyl)oxy)pentanedioic acid:
Figure imgf000041_0003
(S)-2-((S)-1-carboxy-3-methylbutylcarbamoyloxy)pentanedioic acid:
Figure imgf000041_0004
Accordingly, in some embodiments, the presently disclosed subject matter provides a method for treating visceral pain, the method comprising administering to a subject in need of treatment thereof, a GCPII inhibitor disclosed herein. In some embodiments, method of treatment lessens the severity of visceral pain in the subject. In some embodiments, the visceral pain includes abdominal pain. In certain embodiments, the visceral pain is associated with pain originating from one or more organs selected from the stomach, bladder, uterus, rectum, and combinations thereof. In certain embodiments, the visceral pain includes visceral pain from abdominoplasty. In some embodiments, the visceral pain is acute visceral pain. In other embodiments, the visceral pain is chronic visceral pain. In some embodiments, the GCPII inhibitor is administered orally. In certain embodiments, the visceral pain is associated with an elevated level of GCPII in the subject in need of treatment compared to a control subject not afflicted with the condition, disease, or disorder. As used herein, the term “elevated,” as in “an elevated level of GCPII,” refers to a level of GCPII in a subject having or suspected of having a disease, disorder, or condition associated with an elevated level of GCPII compared to a level of GCPII in a normal subject, i.e., a subject who does not have or is not suspected of having a disease, disorder, or condition associated with an elevated level of GCPII, such as an increase of approximately 50%, 100%, 200%, 300%, 400%, 500%, or more. In some embodiments, performing the presently disclosed method results in inhibiting GCPII activity in a subject. As used herein, the term “inhibit” means to decrease or diminish the nSMase2 activity found in a subject, e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 985, 99%, or 100% of the nSMase2 activity compared to an untreated control subject or a subject without the disease or disorder. The term “inhibit” also may mean to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease, disorder, As used herein, the term “treating” can include reversing, alleviating, inhibiting the progression of, preventing, or reducing the likelihood of the disease, disorder, or condition to which such term applies, or one or more symptoms or manifestations of such disease, disorder, or condition. Preventing refers to causing a disease, disorder, condition, or symptom or manifestation of such, or worsening of the severity of such, not to occur. Accordingly, the presently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the disease, disorder, or condition. The “subject” treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term “subject.” Accordingly, a “subject” can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes. Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like. An animal may be a transgenic animal. In some embodiments, the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Further, a “subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease. Thus, the terms “subject” and “patient” are used interchangeably herein. The term “subject” also refers to an organism, tissue, cell, or collection of cells from a subject. In general, the “effective amount” of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the makeup of the pharmaceutical composition, the target tissue, and the like. The term “combination” is used in its broadest sense and means that a subject is administered at least two agents, more particularly a compound disclosed herein and at least one other therapeutic agent. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of a, e.g., single disease state. As used herein, the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days. In one embodiment of the presently disclosed subject matter, the active agents are combined and administered in a single dosage form. In another embodiment, the active agents are administered in separate dosage forms (e.g., wherein it is desirable to vary the amount of one but not the other). The single dosage form may include additional active agents for the treatment of the disease state. Further, the compounds disclosed herein can be administered alone or in combination with adjuvants that enhance stability of the compounds, alone or in combination with one or more therapeutic agents, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. The timing of administration of a compound disclosed herein and at least one additional therapeutic agent can be varied so long as the beneficial effects of the combination of these agents are achieved. Accordingly, the phrase “in combination with” refers to the administration of a compound described herein and at least one additional therapeutic agent either simultaneously, sequentially, or a combination thereof. Therefore, a subject administered a combination of a compound described herein and at least one additional therapeutic agent can receive a compound and at least one additional therapeutic agent at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in either order, on the same day or on different days), so long as the effect of the combination of both agents is achieved in the subject. When administered sequentially, the agents can be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer of one another. In other embodiments, agents administered sequentially, can be administered within 1, 5, 10, 15, 20 or more days of one another. Where the compound described herein and at least one additional therapeutic agent are administered simultaneously, they can be administered to the subject as separate pharmaceutical compositions, each comprising either a compound or at least one additional therapeutic agent, or they can be administered to a subject as a single pharmaceutical composition comprising both agents. When administered in combination, the effective concentration of each of the agents to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent. The effects of multiple agents may, but need not be, additive or synergistic. The agents may be administered multiple times. In some embodiments, when administered in combination, the two or more agents can have a synergistic effect. As used herein, the terms “synergy,” “synergistic,” “synergistically” and derivations thereof, such as in a “synergistic effect” or a “synergistic combination” or a “synergistic composition” refer to circumstances under which the biological activity of a combination of a compound described herein and at least one additional therapeutic agent is greater than the sum of the biological activities of the respective agents when administered individually. Synergy can be expressed in terms of a “Synergy Index (SI),” which generally can be determined by the method described by F. C. Kull et al., Applied Microbiology 9, 538 (1961), from the ratio determined by: Qa/QA + B/QB = Synergy Index (SI) wherein: QA is the concentration of a component A, acting alone, which produced an end point in relation to component A; Qa is the concentration of component A, in a mixture, which produced an end point; QB is the concentration of a component B, acting alone, which produced an end point in relation to component B; and Qb is the concentration of component B, in a mixture, which produced an end point. Generally, when the sum of Qa/QA and Qb/QB is greater than one, antagonism is indicated. When the sum is equal to one, additivity is indicated. When the sum is less than one, synergism is demonstrated. The lower the SI, the greater the synergy shown by that particular mixture. Thus, a “synergistic combination” has an activity higher that what can be expected based on the observed activities of the individual components when used alone. Further, a “synergistically effective amount” of a component refers to the amount of the component necessary to elicit a synergistic effect in, for example, another therapeutic agent present in the composition. Depending on the specific conditions being treated, the “agent(s)” may be formulated into liquid or solid dosage forms and administered systemically or locally. The agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, intra-sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery. For injection, the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the disclosure into dosages suitable for systemic administration is within the scope of the disclosure. With proper choice of carrier and suitable manufacturing practice, the compositions of the present disclosure, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject (e.g., patient) to be treated. For nasal or inhalation delivery, the agents of the disclosure also may be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances, such as saline; preservatives, such as benzyl alcohol; absorption promoters; and fluorocarbons. In particular embodiments, the compound disclosed herein is administered intranasally in a form selected from the group consisting of a nasal spray, a nasal drop, a powder, a granule, a cachet, a tablet, an aerosol, a paste, a cream, a gel, an ointment, a salve, a foam, a paste, a lotion, a cream, an oil suspension, an emulsion, a solution, a patch, and a stick. As used herein, the term administrating via an "intranasal route" refers to administering by way of the nasal structures. Pharmaceutical compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, the bioavailability of the compound(s), the adsorption, distribution, metabolism, and excretion (ADME) toxicity of the compound(s), and the preference and experience of the attending physician. In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions. Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethyl-cellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added. Further, one of ordinary skill in the art will recognize that the presently disclosed compounds, and pharmaceutical compositions thereof, include pharmaceutically acceptable salts. Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and include salts of active compounds that can be prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein. The parent form of the compound can differ from the various salt forms in certain physical properties, such as solubility, and the like. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent or by ion exchange, whereby one basic counterion (base) in an ionic complex is substituted for another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, magnesium, and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange, whereby one acidic counterion (acid) in an ionic complex is substituted for another. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, organic acids, and amino acids. See, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Compounds containing both basic and acidic functionalities allow such compounds to be converted into either base or acid addition salts. Accordingly, pharmaceutically acceptable salts suitable for use with the presently disclosed subject matter include, by way of example but not limitation, acetate, arginate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, monohydrogencarbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, galactonate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydriodic, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate, phthalate, diphosphate, monohydrogen phosphate, dihydrogen phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, suberate, succinate, sulfate, monohydrogensulfate, tannate, tartrate, including (+)-tartrates, (-)-tartrates, and mixtures thereof including racemic mixtures, teoclate, p-toluenesulfonate and trifluoroacetate. Other pharmaceutically acceptable salts may be found in, for example, Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Unless otherwise noted, the chemical definitions provided immediately herein below are intended to comply with IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). The term “hydrocarbon” as used herein, refers to any chemical group comprising hydrogen and carbon. A hydrocarbon group may be substituted or unsubstituted. As would be known to one of ordinary skill in the art, all valencies must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl”, “cycloaliphatic”, or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 alipatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. The term “alkane” refers to acyclic branched or unbranched hydrocarbons having the general formula CnH2n+2, and therefore consisting entirely of hydrogen atoms and saturated carbon atoms. The term “alkyl” refers to a univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom and having the chemical formula of -CnH2n+1. The groups derived by removal of a hydrogen atom from a terminal carbon atom of unbranched alkanes form a subclass of normal alkyl (n-alkyl) groups H(CH2)n. The groups RCH2, R2CH (R ≠ H), and R3C (R ≠ H) are primary, secondary and tertiary alkyl groups, respectively. An alkyl can be a straightchain (i.e., unbranched) or branched acyclic hydrocarbon having the number of carbon atoms designated (i.e., C1-10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In particular embodiments, the term “alkyl” refers to C1-20 inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons. In other embodiments, the alkyl can be a C1-C4 alkyl, including 1, 2, 3, and 4 carbons. In yet other embodiments, the alkyl can be a C1-C6 alkyl, including 1, 2, 3, 4, 5, and 6 carbons. In even yet other embodiments, the alkyl can be a C1-C8 alkyl, including 1, 2, 3, 4, 5, 6, 7, and 8 carbons. “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, “alkyl” refers to straight-chain alkyls. In other embodiments, “alkyl” refers to branched alkyls. In certain other embodiments, “alkyl” refers to straight-chain and/or branched alkyls. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, and dodecyl. Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more substituents, which can be the same or different. Such substituent groups include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, halogen, acyl, carboxyl, oxo, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto. The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain having from 1 to 20 carbon atoms or heteroatoms consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH- CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)- CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The term “cycloalkane” refers to saturated monocyclic hydrocarbons (with or without side chains), e.g., cyclobutane. Unsaturated monocyclic hydrocarbons having one endocyclic double or one triple bond are called cycloalkenes and cycloalkynes, respectively. Those having more than one such multiple bond are cycloalkadienes, cycloalkatrienes, and the like. The inclusive terms for any cyclic hydrocarbons having any number of such multiple bonds are cyclic olefins or cyclic acetylenes. The term “cycloalkyl” refer to a univalent group derived from a cycloalkane by removal of a hydrogen atom from a ring carbon atom. Cycloalkyls can be a mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group also can be optionally substituted with a substituent group provided hereinabove for alkyl groups. Representative monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, and fused ring systems, such as dihydro- and tetrahydronaphthalene, and the like. The term “cycloalkylalkyl” as used herein, refers to a cycloalkyl group, which is attached to the parent molecular moiety through an alkylene moiety, also as defined above, e.g., a C1-20 alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl. The terms “cycloheteroalkyl” and “heterocycloalkyl” (or more generally “heterocyclic”) are used interchangeably and refer to an unsaturated ring system, such as a 3- to 10-member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), in which the nitrogen, sulfur, and phosphorus heteroatoms may be oxidized and the nitrogen heteroatom may be quaternized. The cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings. Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like. The terms “cycloalkylene” and “heterocycloalkylene” refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively. As used herein the terms “bicycloalkyl” and “bicycloheteroalkyl” refer to two cycloalkyl or cycloheteroalkyl groups that are bound to one another. Non-limiting examples include bicyclohexane and bipiperidine. An “unsaturated hydrocarbon” has one or more double bonds or triple bonds. As used herein, the term “alkene” refers to an acyclic branched or unbranched hydrocarbons having one carbon–carbon double bond and the general formula CnH2n. Acyclic branched or unbranched hydrocarbons having more than one double bond are alkadienes, alkatrienes, and the like. More particularly, the term “alkenyl” as used herein refers to a monovalent group derived from a C2-20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule. Alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), 2-propenyl, butenyl, 1-methyl-2-buten-1- yl, pentenyl, 2-isopentenyl, hexenyl, octenyl, allenyl, butadienyl, crotyl (but-2-en-1-yl), 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), and the like, including higher homologs and isomers. The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3- cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl. The term “alkyne” as used herein refers to an acyclic branched or unbranched hydrocarbons having a carbon-carbon triple bond and the general formula CnH2n-2, RC≡CR. Acyclic branched or unbranched hydrocarbons having more than one triple bond are known as alkadiynes, alkatriynes, and the like. The term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C2-20 hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, and the like. As used herein, the term “alkylene” refers to an alkanediyl group having the free valencies on adjacent carbon atoms, e.g. –CH(CH3)CH2– propylene (systematically called propane-1,2-diyl). More particularly, the term “alkylene” by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group also can be optionally unsaturated and/or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (–CH2–); ethylene (– CH2–CH2–); propylene (–(CH2)3–); cyclohexylene (–C6H10–); –CH=CH–CH=CH–; – CH=CH–CH2–; -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, - CH2CH2CH(CH2CH2CH3)CH2-, -(CH2)q-N(R)-(CH2)r–, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (–O–CH2– O–); and ethylenedioxyl (-O-(CH2)2–O–). An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term “heteroalkylene” by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)OR’- represents both -C(O)OR’- and –R’OC(O)-. The term “arene” refers to a monocyclic and polycyclic aromatic hydrocarbon. The term “aryl” refers to a group derived from arenes by removal of a hydrogen atom from a ring carbon atom. Groups similarly derived from heteroarenes are sometimes subsumed in this definition. An aryl group can include, for example, a single ring or multiple rings (such as from 2 to 3 rings), which are fused together or linked covalently. The term “heteroaryl” refers to a group formed by removing one or more hydroxy groups from oxoacids that have the general structure RkE(=O)l(OH)m (l ≠ 0), and replacement analogues of such acyl groups. In organic chemistry an unspecified acyl group is commonly a carboxylic acyl group. The term “heteroaryl” refers to the class of heterocyclyl groups derived from heteroarenes by removal of a hydrogen atom from any ring atom. A “heteroaryl” group can include from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms “arylene” and “heteroarylene” refer to the divalent forms of aryl and heteroaryl, respectively. For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the terms “arylalkyl” and “heteroarylalkyl” are meant to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like). However, the term “haloaryl,” as used herein is meant to cover only aryls substituted with one or more halogens. Where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g. “3 to 7 membered”), the term “member” refers to a carbon or heteroatom. Each of above terms defined hereinabove (e.g. , “alkyl,” “heteroalkyl,” “cycloalkyl, and “heterocycloalkyl”, “alkenyl”, “alkynyl,” “aryl,” “heteroaryl,” as well as their divalent derivatives) are meant to include both substituted and unsubstituted forms of the indicated group. Optional substituents for each type of group are provided below. As used herein, the term “acyl” refers to a group formed by removing one or more hydroxy groups from oxoacids that have the general structure RkE(=O)l(OH)m (l ≠ 0), and replacement analogues of such acyl groups. In organic chemistry an unspecified acyl group is commonly a carboxylic acyl group. For example, in some embodiments, the term acyl includes an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent and has the general formula RC(=O)-, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocylic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes arylacyl groups, such as a 2-(furan-2- yl)acetyl)- and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also are intended to include amides, -RC(=O)NR’, esters, -RC(=O)OR’, ketones, -RC(=O)R’, and aldehydes, -RC(=O)H. The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl–O–) or unsaturated (i.e., alkenyl–O– and alkynyl–O–) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C1-20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n- pentoxyl, neopentoxyl, n-hexoxyl, and the like. The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group. “Aryloxyl” refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl. “Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl. “Aralkyloxyl” refers to an aralkyl-O– group wherein the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl, i.e., C6H5-CH2-O-. An aralkyloxyl group can optionally be substituted. “Alkoxycarbonyl” refers to an alkyl-O-C(=O)– group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert- butyloxycarbonyl. “Aryloxycarbonyl” refers to an aryl-O-C(=O)– group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl. “Aralkoxycarbonyl” refers to an aralkyl-O-C(=O)– group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl. The term “acyloxyl” refers to an oxygen-centered radicals consisting of an acyl radical bonded to an oxygen atom, e.g., an acyl-O- group wherein acyl is as previously described. The term “amine” refers to a compound formally derived from ammonia by replacing one, two or three hydrogen atoms by hydrocarbyl groups, and having the general structures RNH2 (primary amines), R2NH (secondary amines), R3N (tertiary amines). In some embodiments, the term amino refers to the –NH2 group. More generally, the amino group is -NR'R”, wherein R' and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The terms “acylamino” and “alkylamino” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively. An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure –NHR’ wherein R’ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure –NR’R”, wherein R’ and R” are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure –NR’R”R”’, wherein R’, R”, and R’” are each independently selected from the group consisting of alkyl groups. Additionally, R’, R”, and/or R’” taken together may optionally be –(CH2)k– where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino. The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl–S–) or unsaturated (i.e., alkenyl–S– and alkynyl–S–) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like. “Acylamino” refers to an acyl-NH– group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH– group wherein aroyl is as previously described. The term “carbonyl” refers to a compound containing the carbonyl group, -C(=O)-. The term is commonly used in the restricted sense of aldehydes (R-C(=O)H) and ketones, although it actually includes carboxylic acids and derivatives. The term “carboxylic acid” refers to an oxoacids having the structure RC(=O)OH. The term is used as a suffix in systematic name formation to denote the –C(=O)OH group including its carbon atom. In some embodiments, the term “carboxyl” refers to the –COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety. “Carbamoyl” refers to an amide group of the formula –C(=O)NH2. “Alkylcarbamoyl” refers to a R’RN–C(=O)– group wherein one of R and R’ is hydrogen and the other of R and R’ is alkyl and/or substituted alkyl as previously described. “Dialkylcarbamoyl” refers to a R’RN–C(=O)– group wherein each of R and R’ is independently alkyl and/or substituted alkyl as previously described. The term carbonyldioxyl, as used herein, refers to a carbonate group of the formula - O-C(=O)-OR. The term “cyano” refers to the -C≡N group. The terms “halo,” “halide,” or “halogen” as used herein refer to fluoro, chloro, bromo, and iodo groups. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-4)alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like. The term “hydroxyl” refers to the –OH group. The term “hydroxyalkyl” refers to an alkyl group substituted with an –OH group. The term “mercapto” refers to the –SH group. The term “oxo compound” refers to a compounds containing an oxygen atom, =O, doubly bonded to carbon or another element. The term thus embraces aldehydes, carboxylic acids, ketones, sulfonic acids, amides and esters. Oxo used as an adjective (and thus separated by a space) modifying another class of compound, as in oxo carboxylic acids, indicates the presence of an oxo substituent at any position. To indicate a double-bonded oxygen that is part of a ketonic structure, the term keto is sometimes used as a prefix, but such use has been abandoned by IUPAC for naming specific compounds. A traditional use of keto is for indicating oxidation of CHOH to C=O in a parent compound that contains OH groups, such as carbohydrates, e.g. 3-ketoglucose. In some embodiments, the term “oxo” as used herein means an oxygen atom that is double bonded to a carbon atom or to another element. The term “nitro” refers to the –NO2 group. The term “thio” refers to replacement of an oxygen by a sulfur, e.g., PhC(=S)NH2, thiobenzamide. The term “thiol” refers to a compounds having the structure RSH (R ≠ H), e.g., MeCH2SH ethanethiol. A thiol also is known by the term “mercaptan.” The term “thiohydroxyl” or “thiol,” as used herein, refers to a group of the formula – SH. The term “sulfate” refers to the –SO4 group. The term “sulfide” refers to a compound having the structure RSR (R ≠ H) and also are referred to as “thioethers.” The term “sulfone” refers to a compound having the structure, RS(=O)2R (R ≠ H), e.g., C2H5S(=O)2CH3 ethyl methyl sulfone. The term “sulfoxide” refers to a compound having the structure R2S=O (R ≠ H), e.g., Ph2S=O diphenyl sulfoxide. The term “ureido” refers to a urea group of the formula –NH—CO—NH2. One of ordinary skill in the art would recognize that a structure represented generally by, for example, the formula:
Figure imgf000059_0001
as used herein refers to a ring structure, for example, but not limited to a 3-carbon, a 4- carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and/or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and number of R groups is determined by the value of the variable “n,” which is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution. Each R group, if more than one, is substituted on an available carbon of the ring structure rather than on another R group. For example, the structure above where n is 0 to 2 would comprise compound groups including, but not limited to: and the like.
Figure imgf000060_0001
A dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure. The symbol ( ) denotes the point of attachment of a moiety to the remainder of the molecule.
Figure imgf000060_0002
When a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as being “absent,” the named atom is replaced by a direct bond. Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist. Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. As used herein, the term “congener” refers to one of two or more substances related to each other by origin, structure, or function. The term “enantiomer” refers to one of a pair of molecular entities which are mirror images of each other and non-superposable. The term “stereoisomer” refers to an isomer that possess identical constitution, but which differ in the arrangement of their atoms in space. The term “racemate” refers to an equimolar mixture of a pair of enantiomers. It does not exhibit optical activity. The chemical name or formula of a racemate is distinguished from those of the enantiomers by the prefix (±)- or rac- (or racem-) or by the symbols RS and SR. The term “diastereoisomerism” refers to stereoisomerism other than enantiomerism. Diastereoisomers (or diastereomers) are stereoisomers not related as mirror images. Diastereoisomers are characterized by differences in physical properties, and by some differences in chemical behavior towards achiral as well as chiral reagents. It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. Following long-standing patent law convention, the terms “a,” “an,” and “the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a subject” includes a plurality of subjects, unless the context clearly is to the contrary (e.g., a plurality of subjects), and so forth. Throughout this specification and the claims, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term “include” and its grammatical variants are intended to be non- limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items. For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, quantities, characteristics, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about” even though the term “about” may not expressly appear with the value, amount or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are not and need not be exact, but may be approximate and/or larger or smaller as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art depending on the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term “about,” when referring to a value can be meant to encompass variations of, in some embodiments, ± 100% in some embodiments ± 50%, in some embodiments ± 20%, in some embodiments ± 10%, in some embodiments ± 5%, in some embodiments ±1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions. Further, the term “about” when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range. EXAMPLES The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The descriptions and specific examples that follow are only intended for the purposes of illustration, and are not to be construed as limiting in any manner. EXAMPLE 1 Inhibition of GCPII in the Enteric Nervous System as a Novel Therapeutic for Visceral Pain 1.1 GCPII modulates glutamate signaling and its inhibition is analgesic in peripheral pain models GCPII catalyzes the hydrolysis of the abundant neuropeptide N- acetylaspartylglutamate (NAAG) to glutamate (FIG. 1). Not only does GCPII inhibition decrease glutamate levels derived from NAAG, but it also elevates NAAG levels, which is an agonist at pre-synaptic metabotropic glutamate 3 receptors (mGluR3) and serves to inhibit glutamate release. The clinical relevance of this pathway is evidenced by the widespread interest in developing analgesic drugs specifically targeting NAAG/glutamate conversion or attenuating excess glutamate signaling. Fundytus, 2001; Wozniak et al., 2012a. Indeed, GCPII inhibitors and various agonists/antagonists of ionotropic and metabotropic glutamate receptors (iGluR/mGluR) have demonstrated analgesic activity in diverse rodent models of both acute and chronic pain, including models of thermal hyperalgesia, mechanical allodynia, neuropathic pain, and inflammatory pain. Vornov et al., 2016. Without wishing to be bound to any one particular theory, it was thought that GCPII inhibition could have analgesic activity in visceral pain. Although glutamatergic signaling pathways have received lesser characterization in the enteric nervous system (ENS), all subtypes of mGluRs and iGluRs present in the CNS/PNS have been identified in mammalian gastrointestinal tissues, Baj et al., 2019. Recent studies also have shown that glutamate secreted by colon epithelial EECs can activate vagal afferents, Kaelberer et al., 2018, suggesting that epithelial-derived glutamate may be a key player in visceral pain signaling. Najjar et al., 2020. Thus, it was thought that inhibiting GCPII with small molecule inhibitors might attenuate visceral pain, including abdominal pain. 1.2 Visceral Pain is a large unmet medical need There is a large unmet clinical need for non-addictive analgesic agents to treat visceral pain, defined as the pain emanating from internal organs, including, but not limited to, the stomach, bladder, pancreas, abdomen and rectum. Recently, the National Gastrointestinal (GI) Survey, a patient-reported outcomes measures (PROM) assessment of GI symptoms in 71,000 Americans, found that 61% of all surveyed persons reported having at least one GI symptom in the past week. Almario et al., 2018. Abdominal pain was the second most prevalent symptom and was reported by a staggering 24.8% of participants. Almario et al., 2018. Given this high incidence in the general population, it is unsurprising that abdominal pain is a frequent and debilitating symptom in patients with diagnosed GI and genitourinary diseases. To exemplify this, in Inflammatory Bowel Disease (IBD), 80% of patients report acute pain during symptom flares and as many as 30-50% develop chronic pain that persists even during periods of inflammatory remission. Hurtado-Lorenzo et al., 2021; Szigethy, 2018. In Irritable Bowel Syndrome (IBS), 75% of patients report continuous or frequent abdominal pain, with pain listed as a primary factor making their IBS severe. Drossman et al., 2009. In endometriosis, recurrent abdominal pain often persists following conventional surgical and/or hormonal therapies, with no satisfactory options for pain management in affected patients. Mechsner, 2022. In chronic pancreatitis, visceral pain is a defining symptom reported by >90% of patients, and opioid analgesics are still widely used in pain management after failure of existing non-opioid agents. Gardner et al., 2020; Bhardwaj et al., 2009. 1.3 Two chemically distinct GCPII inhibitors (IBD3540 and JHU241) are robustly analgesic in preclinical visceral pain models Referring now to FIG. 2, FIG. 3, and FIG. 4, IBD3540 and JHU 241 attenuate visceral pain in the following chronic visceral hypersensitivity (CVH) models: (1) surgically induced TNBS-CVH of adult rats (IBD3540 and JHU 241); (2) enema induced AA-CVH of juvenile mice (IBD3540 only); and (3) enema induced TNBS- CVH of adult mice (IBD3540 only). IBD3540 and JHU 241 were first evaluated in a rat model of CVH, in which a surgical administration of caustic chemical 2,4,6-trinitrobenzene sulfonic acid (TNBS) in the proximal colon results in hypersensitization to balloon colorectal distension (CRD). In this model, both oral IBD3540 (275 mg/kg) and oral JHU 241 (10 mg/kg) displayed strong analgesic efficacy, significantly increasing the colorectal distension (CRD) required to elicit a behavioral pain response (FIG. 4), with comparable effect size to gabapentin under identical experimental conditions (IBD354069.6% improvement vs. JHU 24165.2% improvement vs. gabapentin 59.0% improvement). These data provide the first in vivo evidence that multiple classes of GCPII inhibitors are analgesic in visceral pain. Following this demonstration of positive analgesic efficacy in rat TNBS-CVH, we next evaluated gut-restricted GCPII inhibitor IBD3540 for analgesic activity in a second mechanistically distinct model of CVH, in which juvenile mice are sensitized with a single enema of diluted acetic acid as neonates precipitating visceral hyperresponsivity in adulthood. Salvatierra et al., 2018. As used herein, the term “gut restricted” means that the drug or therapeutic agent stays in the gut with minimal exposure to the rest of the body when given orally, thereby targeting gastrointestinal GCPII while limiting systemic side effects. Oral IBD3540 treatment significantly attenuated reflex contractions of the abdominal oblique muscle (visceromotor response, VMR) to aversive CRD at 30, 50 and 70 mmHg and was found completely attenuate visceral hypersensitivity, at doses as low as 2.75 mg/kg (FIG 5). In agreement with the data from rat surgically-induced TNBS-CVH, when we examined 27.5 mg/kg (S)-IBD3540 PO head-to-head versus positive control 300 mg/kg eq. gabapentin PO, we observed that (S)-IBD3540 was equivalently efficacious to high-dose gabapentin in the AA-CVH model (FIG. 6). The AA-CVH studies in FIG. 5 and FIG. 6 demonstrate potent analgesic efficacy of oral (S)-IBD3540 when administered for an acute, 7-day, period. To assess durability of IBD3540’s analgesic effects, we administered once daily oral 27.5 mg/kg IBD3540 for a chronic, 28-day, period (Fig. 7). No tolerance to repeated dosing was observed; (S)- IBD3540 remained significantly analgesic following chronic administration. Moving forward, we tested (S)-IBD3540 for analgesic efficacy in a third model of rodent-CVH. In this model, TNBS was administered to adult mice via an intrarectal enema, as opposed to a surgical instillation in the proximal colon utilized in the rat TNBS model. Following the TNBS enema the mice are maintained for 6-8 weeks allowing for colon recovery from TNBS-induced chemical injury/ulceration and measurement of visceral hyperalgesia in a post-inflammatory state. Here we tested 2.75 and 27.5 mg/kg eq. PO (S)- IBD3540 head-to-head versus 300 mg/kg PO gabapentin. Again, we observed potent analgesic activity. Both the 2.75 mg/kg and 27.5 mg/kg PO (S)-IBD3540 were significantly analgesic and the magnitude of analgesic efficacy was equivalent to high-dose gabapentin (FIG. 8). Excitingly, in this model we also observed that (S)-IBD3540 attenuated hypersensitivity to baseline levels. 1.4 Methods 1.4.1 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CVH of rats Adult male Sprague-Dawley rats, weighing 390-450 g, were anesthetized with ketamine/xylazine and the colon was visualized. Using a sterile syringe TNBS (50 mg/kg; 1 mL/kg in 25% EtOH) was injected in the proximal colon, 1 cm distal to the caecum. Naïve rats, without surgery, were used as controls. Treatment was initiated approximately 6 hours following surgical recovery. Rats were treated once daily with vehicle, IBD3540 or JHU 241 at doses indicated in figure legends. On the seventh day post-TNBS, colonic sensitivity was assessed by measuring the intracolonic pressure required to induce a pain behavioral response. A 5-cm balloon was inserted through the anus and gently advanced to a 10 cm intracolonic distance. Following a 30-minute acclimation period, the balloon was gradually inflated in 5 mmHg steps every 30 sec, from 5 to a maximum of 75 mmHg. The pressure at which pain behavior was first elicited was recorded; pain behaviors were defined as elevation of the hind part of the animal body (lordosis) with clearly visible abdominal contraction (abdominal cramping). Behavioral responses were assessed by trained investigators blinded to treatment group. 1.4.2 Acetic acid (AA)-induced CVH of mice: Mouse chronic visceral hypersensitivity (CVH) models Neonatal C57BL/6 mice (7-10 days old), both genders, received a single intrarectal enema of vehicle or dilute acetic acid (AA) (0.5% AA, 50 μL) administered to awake mice via lubricated Hamilton syringe. In adulthood (6-8 months of age), mice underwent a brief surgical procedure to implant electrodes in the right abdominal musculature for measurement of abdominal electromyography. Following a 72-h surgical recovery period, mice were randomized to treatment groups, and were then treated once daily for 7 days (acute) or 28 days (chronic) with vehicle, gabapentin, or IBD3540 at doses indicated in figure legends. 60 minutes after the final dose visceromotor response to graded colorectal distension was measured using defined pressures of 15, 30, 50 and 70-mm Hg. All measurements were made in duplicate. (n=5-6/group; 2-way ANOVA with Newman-Keuls post-hoc analysis, & p<0.001, * p< 0.05, **p<0.01). 1.4.3 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CVH of mice 7-week-old BALB/c mice, both genders, were anesthetized with vaporized isoflurane and a single intrarectal administration of 60 uL 2.5% w/v TNBS in 50% EtOH was performed by flexible catheterization. Post-sensitization, body weight was monitored daily and those exhibiting characteristic body weight loss (>5% for ≥ 2 consecutive days) were included in experimental cohorts. At 5 weeks post-sensitization, experimental mice underwent surgery to implant electrodes in the right abdominal musculature for measurement of abdominal electromyography. Following a 72h surgical recovery period, mice were randomized to treatment groups, and were then treated once daily for 7 days with vehicle, gabapentin, or IBD3540 at concentrations indicated in figure legends. 60 minutes after the final dose visceromotor response to graded colorectal distension was measured using defined pressures of 15, 30, 50 and 70 mmHg. All measurements were made in duplicate. (n=5-6/group; 2-way ANOVA with Newman-Keuls post-hoc analysis, & p<0.001, * p< 0.05, **p<0.01) REFERENCES All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of those skilled in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that, although a number of patent applications, patents, and other references are referred to herein, such reference does not constitute an admission that any of these documents form part of the common general knowledge in the art. Fundytus ME. Glutamate receptors and nociception: implications for the drug treatment of pain. CNS Drugs 2001;15:29-58. 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Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications can be practiced within the scope of the appended claims.

Claims

THAT WHICH IS CLAIMED: 1. A method for treating visceral pain, the method comprising administering to a subject in need of treatment thereof, a GCPII inhibitor. 2. The method of claim 1, wherein the GCPII inhibitor is a compound of formula (I): wherein:
Figure imgf000073_0001
R1 and R2 are each independently H or -OH; R3 is OH; and R4 is selected from the group consisting of -NH-X1, -COO-X1, -C(=O)-NH-CH2- C(=O)-O-X1, and -C(=O)-NH-CH2-CH2-S(=O)2-O-X1,wherein X1 is selected from the group consisting of -(C=O)-(CH2)m-P(=O)(OH)-X2, -(C=O)-(CH2)m-CH(COOH)-CH2-P(=O)(OH)- X2, -CH2-O-(C=O)-(CH2)m-P(=O)(OH)-X2, -CH2-O-C(=O)-(CH2)m-CH(COOH)-CH2- P(=O)(OH)-X2, -CH2-O-C(=O)-(CH2)m-CH(COOH)-NH-(C=O)-NH-CH(COOH)-CH2- CH(CH3)2, -CH2-O-C(=O)-Ar-CH2-CH(COOH)-(CH2)m-C(=O)-NH-OH, -CH2-O-C(=O)- (CH2)m-X3, -CH2-O-C(=O)-Ar-CH2-X3, and a protecting group, wherein X2 is selected from the group consisting of -OH, -CH2-CH(COOH)-(CH2)p-C(=O)-OH, and a protecting group, Ar is arylene, and X3 is 2-oxotetrahydro-2H-thiopyran-3-yl, and each m and p is independently selected from the group consisting of 1, 2, 3, and 4; or R3 is selected from the group consisting of -O-C(=O)-O-CH2-O-C(=O)-(CH2)n- CH(COOH)-CH2-P(=O)(OH)2, and -O-C(=O)-CH2-CH2-P(=O)(OH)-CH2-CH(COOH)- (CH2)n-C(=O)-OH, wherein each n is independently an integer selected from the group consisting of 1,
2, 3, and 4; and R4 is selected from the group consisting of -NH2, -COOH, -C(=O)-NH-CH2-C(=O)- OH, and -C(=O)-NH-CH2-CH2-S(=O)2-OH; and pharmaceutically acceptable salts thereof.
3. The method of claim 2, wherein: (i) R1 and R2 are both H; (ii) R1 is H and R2 is OH; (iii) R1 is OH and R2 is H; or (iv) R1 and R2 are both OH.
4. The method of claim 2, wherein: (i) R3 is OH and R4 is selected from the group consisting of -NH-X1, -COO-X1, - C(=O)-NH-CH2-C(=O)-O-X1, and -C(=O)-NH-CH2-CH2-S(=O)2-O-X1, wherein X1 is selected from the group consisting of -(C=O)-CH2-CH2-P(=O)(OH)-X2, -(C=O)-CH2-CH2- CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O-(C=O)-CH2-CH2-P(=O)(OH)-X2, -CH2-O-C(=O)- CH2-CH2-CH(COOH)-CH2-P(=O)(OH)-X2, -CH2-O-C(=O)-CH2-CH2-CH(COOH)-NH- (C=O)-NH-CH(COOH)-CH2-CH(CH3)2, -CH2-O-C(=O)-Ar-CH2-CH(COOH)-CH2CH2- C(=O)-NH-OH, -CH2-O-C(=O)-CH2-CH2-X3, -CH2-O-C(=O)-Ar-CH2-X3, and a protecting group, wherein X2 is selected from the group consisting of -OH, -CH2-CH(COOH)-CH2- CH2-CH(=O)-OH, and a protecting group, Ar is phenyl, and X3 is 2-oxotetrahydro-2H- thiopyran-3-yl; (ii) R1 is OH, R2 is H, R3 is OH, and R4 is COO-X1, wherein X1 is -CH2-O-C(=O)- (CH2)m-CH(COOH)-CH2-P(=O)(OH)-X2; or (iii) R1 is H and R2 is OH or R1 is OH and R2 is H, R3 is OH, and R4 is -NH-X1, wherein X1 is -(C=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)-X2.
5. The method of claim 2, wherein the compound of formula (I) is selected from the group consisting of:
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
6. The method of claim 2, wherein R3 is selected from the group consisting of - O-C(=O)-O-CH2-O-C(=O)-CH2-CH2-CH(COOH)-CH2-P(=O)(OH)2, and -O-C(=O)-CH2- CH2-P(=O)(OH)-CH2-CH(COOH)-CH2-CH2-C(=O)-OH, and R4 is selected from the group consisting of -NH2, -COOH, -C(=O)-NH-CH2-C(=O)-OH, and -C(=O)-NH-CH2-CH2- S(=O)2-OH.
7. The method of claim 2, wherein the compound of formula (I) is selected from the group consisting of:
Figure imgf000077_0001
8. The method of claim 1, wherein the GCPII inhibitor is a hydroxamate-based GCPII inhibitor of formula (IIa):
Figure imgf000077_0002
wherein n is an integer selected from 0, 1, 2, and 3.
9. The method of claim 8, wherein the hydroxamate-based GCPII inhibitor comprises:
Figure imgf000077_0003
10. The method of claim 1, wherein the GCPII inhibitor is a prodrug of a hydroxamate-based GCPII inhibitor of formula (IIb): wherein:
Figure imgf000078_0001
R1 is selected from the group consisting of -C(=O)-O-R4 and -Ar-C(=O)-O-R4; R2 is selected from the group consisting of H, substituted and unsubstituted C1-C6 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C12 aryl, substituted and unsubstituted C6-C12 heteroaryl, -(CR5R6)n-R7, -C(=O)-O-R7, -C(=O)- R7,-C(=O)-NR7R8, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7; R3 is selected from the group consisting of H, substituted and unsubstituted C1-C6 alkyl, substituted and unsubstituted C3-C12 cycloalkyl, substituted and unsubstituted C6-C12 aryl, substituted and unsubstituted C5-C12 heteroaryl; R4 is selected from the group consisting of H, substituted and unsubstituted C1-C6 alkyl, substituted and unsubstituted C3-C12 cycloalkyl, substituted and unsubstituted C6-C12 aryl, substituted and unsubstituted C5-C12 heteroaryl, -(CR5R6)n-O-C(=O)-O-R9, and - (CR5R6)n-Ar-O-C(=O)-R9; each R5 and R6 is independently selected from the group consisting of H, C1-C10 alkyl, and C6-C12 aralkyl; R7 is selected from the group consisting of H, and substituted and unsubstituted C1- C10 alkyl, substituted and unsubstituted C1-C10 heteroalkyl, substituted and unsubstituted C3- C16 cycloalkyl, substituted and unsubstituted C3-C12 cycloheteroalkyl, substituted and unsubstituted C3-C12 cycloheteroalkenyl, substituted and unsubstituted C6-C12 aryl, substituted and unsubstituted C6-C12 heteroaryl, and substituted and unsubstituted C6-C12 aralkyl; R8 is selected from the group consisting of H, and substituted and unsubstituted C1- C6 alkyl; R9 is selected from the group consisting of H, and substituted and unsubstituted C1- C6 alkyl; n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; Ar is selected from the group consisting of substituted and unsubstituted C6-C12 aryl, and substituted and unsubstituted C6-C12 heteroaryl; and stereoisomers and pharmaceutically acceptable salts thereof.
11. The method of claim 10, wherein the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000079_0001
wherein: R2 is selected from the group consisting of substituted and unsubstituted C1-C6 alkyl, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted C6-C12 aryl, substituted and unsubstituted C6-C12 heteroaryl, -(CR5R6)n-R7, -C(=O)-O-R7, -C(=O)-R7,- C(=O)-NR7R8, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7; R3 is selected from the group consisting of H and substituted and unsubstituted C1-C6 alkyl; R4 is selected from the group consisting of H, substituted and unsubstituted C1-C6 alkyl, -(CR5R6)n-Ar-O-C(=O)-R9, and -(CR5R6)n-O-C(=O)-O-R9; wherein n is 1, R5 and R6 are H, Ar is phenyl, R9 is selected from the group consisting of substituted C1-C3 alkyl, and unsubstituted C1-C3 alkyl; and stereoisomers and pharmaceutically acceptable salts thereof.
12. The method of claim 10, wherein R2 is -(CR5R6)n-Ar-O-C(=O)-R7, n is 1, Ar is phenyl, and R7 is substituted or unsubstituted C1-C6 alkyl.
13. The method of claim 10, wherein the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000080_0001
14. The method of claim 10, wherein R2 is -(CR5R6)n-R7 , n is 1, and R7 is substituted C3-C12 cycloheteroalkenyl.
15. The method of claim 10, wherein the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000081_0001
16. The method of claim 10, wherein R2 is -C(=O)-R7, and R7 is unsubstituted C1- C6 alkyl, substituted C1-C6 alkyl, unsubstituted C6-C12 aryl, or unsubstituted C6-C12 aralkyl.
17. The method of claim 10, wherein the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000081_0002
Figure imgf000082_0001
18. The method of claim 10, wherein R2 is -C(=O)-O-R7, and R7 is unsubstituted C1-C6 alkyl.
19. The method of claim 10, wherein the compound of formula (IIb) is:
Figure imgf000083_0001
20. The method of claim 10, wherein R2 is -C(=O)-NR7R8, R7 is substituted C1- C6 alkyl, or substituted C3-C16 cycloalkyl, and R8 is H.
21. The method of claim 10, wherein the compound of formula (IIb) is selected from the group consisting of:
Figure imgf000083_0002
22. The method of claim 10, wherein the compound of formula (IIb) is:
.
Figure imgf000084_0001
23. The method of claim 1, wherein the GCPII inhibitor is a compound of formula (IIIa) or (IIIb):
Figure imgf000084_0002
wherein: each R1, R2, R3, and R4 is independently selected from the group consisting of H, alkyl, Ar, -( CR5R6)n-Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n-C(=O)-O-R7, -(CR5R6)n-O- C(=O)-O-R7,-(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7,- Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9, wherein n is an integer from 1 to 20, m is an integer from 1 to 20; each R3' and R4' are independently H or alkyl; each R5 and R6 is independently selected from the group consisting of H, alkyl, and alkylaryl; each R7 is independently straightchain or branched alkyl; Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; and R8 and R9 are each independently H or alkyl; and pharmaceutically acceptable salts thereof.
24. The method of claim 23, wherein the compound of formula (IIIa) is selected from the group consisting of:
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
25. The method of claim 23, wherein compound of formula (IIIb) is selected from:
Figure imgf000089_0002
26. The method of claim 23, wherein: (a) each R1 is H; each R2 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4 is selected from the group consisting of -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, - (CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n- C(=O)-NR8R9; (b) each R1 is alkyl; each R2 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4 is selected from the group consisting of Ar, -(CR5R6)n-O-C(=O)-R7, - (CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n- O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and - (CR5R6)n-C(=O)-NR8R9; (c) each R1 is-(CR5R6)n-Ar; each R2 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4 is selected from the group consisting of Ar, -(CR5R6)n-O-C(=O)-R7, - (CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n- O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and - (CR5R6)n-C(=O)-NR8R9; or (d) each R1 is selected from Ar, -(CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, - (CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar- O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R2 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; each R3 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; and each R4 is selected from the group consisting of H, alkyl, Ar, -(CR5R6)n-Ar, - (CR5R6)n-O-C(=O)-R7, -(CR5R6)n- C(=O)-O-R7, -(CR5R6)n-O-C(=O)-O-R7, -(CR5R6)n-O-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, - (CR5R6)n-NR8R9, and -(CR5R6)n-C(=O)-NR8R9; wherein: each n is an integer from 1 to 20; each m is an integer from 1 to 20; each R5 and R6 is independently selected from the group consisting of H, alkyl, and alkylaryl; each R7 is independently straight chain or branched alkyl; each Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl; each R8 and R9 are independently H or alkyl; and each R3' and R4' are independently H or alkyl; and pharmaceutically acceptable salts thereof.
27. The method of claim 23, wherein the compound is a compound of formula (IIIa) and: R1 is H; R2 and R3 are each selected from the group consisting of H, -(CR5R6)n-O-R7, - (CR5R6)n-Ar-O-C(=O)-R7, -(CR5R6)n-O-C(=O)-R7, -Ar-C(=O)-O-(CR5R6)n-R7, and - (CR5R6)n-O-C(=O)-O-R7; and R4 is selected from the group consisting of -(CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)- R7, -Ar-C(=O)-O-(CR5R6)n-R7, -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof.
28. The method of claim 23, wherein the compound is a compound of formula (IIIa) and: R1 is alkyl; R2 and R3 are each independently selected from the group consisting of H, alkyl, - (CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)-R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-O- C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; and R4 is selected from the group consisting of -(CR5R6)n-O-R7, -(CR5R6)n-Ar-O-C(=O)- R7, -(CR5R6)n-O-[(CR5R6)n-O]m-R7, -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof.
29. The method of claim 23, wherein the compound is a compound of formula (IIIa) and: R1 is selected from -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; and R2 R3, and R4 are each independently selected from H, Ar, -(CR5R6)n-O-C(=O)-R7, and -(CR5R6)n-O-C(=O)-O-R7; and pharmaceutically acceptable salts thereof.
30. The method of claim 23, wherein the compound is a compound of formula (IIIa) and: one of R1, R2, R3, or R4 is H and the other three are each independently selected from the group consisting of: -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; wherein R5 and R6 are each independently selected from the group consisting of H, C1-8 straight-chain alkyl, and C1-8 branched-chain alkyl; R7 is C1-8 straight-chain alkyl, and C1-8 branched-chain alkyl; and pharmaceutically acceptable salts thereof.
31. The method of claim 23, wherein the compound is a compound of formula (IIIa) and: R2 is H; and R1, R3, and R4 are each independently selected from the group consisting of: -(CR5R6)n-O-C(=O)-R7 and -(CR5R6)n-O-C(=O)-O-R7; wherein R5 and R6 are each independently selected from the group consisting of H, C1-8 straight-chain alkyl, and C1-8 branched-chain alkyl; R7 is C1-8 straight-chain alkyl or C1-8 branched-chain alkyl; and pharmaceutically acceptable salts thereof.
32. The method of claim 23, wherein R5 and R6 are each H.
33. The method of claim 1, wherein the GCPII inhibitor is a compound of formula (IV): wherein:
Figure imgf000093_0001
indicates that the bond can be a single or a double bond;
Figure imgf000093_0002
R1 is: -OR5, wherein R5 is selected from the group consisting of H, C1-C8 alkyl, and -O- (CH2)n-R6, wherein n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8 and R6 is substituted or unsubstituted aryl or heteroaryl; or -NR7R8, wherein R7 and R8 are each independently selected from the group consisting of H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C8 alkoxyl, unsubstituted or substituted aryl or heteroaryl, -(CH2)m-R9, wherein R9 is -OR10 or CHX2, wherein R10 is H or C1-C4 alkyl, and each X is halogen, and -(CH2)m-CH(NH2)(COOH), wherein each m is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; R2 is H or -NR11R12, wherein R11 and R12 are each independently selected from the group consisting of H, C1-C4 alkyl, and -C(=O)-R13, wherein R13 is C1-C4 alkyl or -C(NH2)-(CH2)p-R14, wherein R14 is C1-C4 alkyl or -NR15R16, wherein R15 and R16 are each H or C1-C4 alkyl, and p is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; R3 and R4 are each independently H or -C(=O)-R17, wherein R17 is C1-C8 alkyl or -(CH2)t-O-C(=O)-O-R18, wherein R18 is C1-C8 alkyl, and t is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; and stereoisomers and pharmaceutically acceptable salts thereof.
34. The method of claim 33, wherein: (i) R1 is -OR5, and R5 is selected from the group consisting of H, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, and n-octyl; (ii) R1 is -OR5, and R5 is H or -O-(CH2)n-R6, wherein R6 is substituted or unsubstituted phenyl; (iii) R1 is -NR7R8, and R7 is H or C1-C4 alkyl and R8 is selected from the group consisting of H, C1-C4 alkyl, C3-C6 cycloalkyl, unsubstituted or substituted phenyl, -(CH2)m- R9, wherein R9 is -OR10 or CHX2, wherein R10 is H or C1-C4 alkyl, and each X is halogen, and -(CH2)m-CH(NH2)(COOH), wherein each m is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; or (iv) R2 is -NR11R12, wherein R11 is H and R12 is H or -C(=O)-R13, wherein R13 is C1- C4 alkyl or -C(NH2)-(CH2)p-R14, wherein R14 is C1-C4 alkyl or -NR15R16, wherein R15 and R16 are each H or C1-C4 alkyl, and p is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.
35. The method of claim 33, wherein: (i) R3 and R4 are each H; (ii) if R1 is -OR5, then R5 cannot be H; or (iii) if R1 is -OR5, then R3, R4, and R5 cannot all be H.
36. The method of claim 33, wherein R3 and R4 are each independently selected from the group consisting of -C(=O)-CH3, -C(=O)-C(CH3)3, and -CH2-O-C(=O)-O- CH(CH3)2.
37. The method of claim 33, wherein the compound of formula (IV) is selected from the group consisting of:
Figure imgf000095_0001
Figure imgf000096_0001
38. The method of claim 1, wherein the GCP-II inhibitor is selected from: 2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[((2-phenylethyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[((3-phenylpropyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[((3-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[((2-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(4-phenylbutyl)hydroxyphosphinyl]methyl]pentanedioic acid; 2-[[(aminomethyl)hydroxyphosphinyl]methyl]pentanedioic acid; 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid; 2-(phosphonomethyl)pentanedioic acid; N-[methylhydroxyphosphinyl]glutamic acid; N-[ethylhydroxyphosphinyl]glutamic acid; N-[propylhydroxyphosphinyl]glutamic acid; N-[butylhydroxyphosphinyl]glutamic acid; N-[phenylhydroxyphosphinyl]glutamic acid; and N-[(phenylmethyl)hydroxyphosphinyl]glutamic acid.
39. The method of claim 1, wherein the GCPII inhibitor is a compound of formula (V’):
Figure imgf000097_0001
wherein R is H or C1-C4 alkyl, and R’ is benzyl; or a compound of formula (V”):
Figure imgf000097_0002
wherein R is selected from H, 4-fluorobenzoyl, and 6-(fluorescein-5-carboxamido)hexanoyl.
40. The method of claim 1, wherein the GCPII inhibitor is selected from 3-(2- mercaptoethyl)biphenyl-2,3-dicarboxylic acid (E2072) and GPI-5693:
Figure imgf000097_0003
41. The method of claim 1, wherein the GCPII inhibitor is selected from MIP- 1555, MIP-1519, MIP-1545, MIP-1427, MIP-1428, MIP-1379, MIP-1072, MIP-1095, MIP- 1558, MIP-1405, MIP-1404, PSMA I&T, PSMA-617, PSMA-11, DCIBzL, 18F-DCFPyl, ZJ 38, GCPII-IN-1, and JB-352. 42. The method of claim 1, wherein the GCPII inhibitor is a dendrimer conjugate of 2-PMPA, 2-MPPA, or other GCPII inhibitor. 43. The method of claim 1, wherein the visceral pain includes abdominal pain. 44. The method of claim 1, wherein the GCPII inhibitor is administered orally.
PCT/US2024/057830 2023-11-28 2024-11-27 Inhibition of gcpii in the enteric nervous system for visceral pain Pending WO2025117800A1 (en)

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