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WO2025097160A1 - Procédés d'amélioration de l'efficacité thérapeutique de la lévodopa - Google Patents

Procédés d'amélioration de l'efficacité thérapeutique de la lévodopa Download PDF

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Publication number
WO2025097160A1
WO2025097160A1 PCT/US2024/054451 US2024054451W WO2025097160A1 WO 2025097160 A1 WO2025097160 A1 WO 2025097160A1 US 2024054451 W US2024054451 W US 2024054451W WO 2025097160 A1 WO2025097160 A1 WO 2025097160A1
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Prior art keywords
mito
compound
dopa
formula
levodopa
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Inventor
Balaraman Kalyanaraman
Micael Joel Hardy
Gang Cheng
Jimmy B. FEIX
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Aix Marseille Universite
Medical College of Wisconsin
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Aix Marseille Universite
Medical College of Wisconsin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings

Definitions

  • L-dopa levodopa
  • L-dopa therapy does not reverse or slow degeneration of dopaminergic neurons in PD, but it significantly reduces motor symptoms and increases quality of life, particularly early in its therapeutic course.
  • L-dopa doses often need to be increased to manage the PD symptoms, resulting in L-dopa-induced dyskinesia (LID).
  • LID which occurs in more than 50% of L-dopa treated patients, is characterized by abnormal and excessive voluntary movements that are so severe that they interfere with gross and fine movements needed for daily life. LIDs present a therapeutic conundrum as their appearance necessitates reducing L-dopa doses, resulting in increased PD symptoms. [0004] Thus, there remains a need for methods of enhancing L-dopa therapeutic efficacy in Parkinson’s disease.
  • the present disclosure provides a method of modulating microbial metabolism of levodopa in gut of a subject in need thereof, the method comprises administering to the subject levodopa and an effective amount of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof,
  • the present disclosure provides a method of treating Parkinson’s disease in a subject in need thereof, the method comprises administering to the subject an effective amount of levodopa and an effective amount of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof,
  • the uptake of levodopa in the brain of the subject is increased and/or formation of dopamine in the brain of the subject is increased.
  • the microbial metabolism of levodopa to dopamine in the gut of the subject is decreased.
  • the levodopa is administered to the subject in a combination with carbidopa.
  • the present disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an effective amount of levodopa, and an effective amount of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof,
  • the pharmaceutical composition further comprises carbidopa.
  • the present disclosure provides a compound of formula (III-a) or (IV-a), or a pharmaceutically acceptable salt thereof, w ere n one of R 3 and R 4 is Mito, the other is –(CH 2 CH 2 O) v –R A ; v is 1-20; R A is H or C 1-4 alkyl; Mito is ; L is C 1-20 alkylene, C 2-20 alkenylene, L 1 -R C -L 2 , or amino acid; L 1 and L 2 are each independently absent or C 1 -C 10 alkylene; R C is –(CH 2 CH 2 O) q –, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently -CF 3 , Me, Cl, OMe, C(O)CH 3 , NO 2 , N(Me) 2
  • the present disclosure provides a compound of formula (V-a) or (VI-a), or a pharmaceutically acceptable salt thereof, wherein each of R 5 and R 6 is –(CH 2 CH 2 O) w –R A or R B ; w is 1-20; Z is NH or O R A is H or C 1-4 alkyl; R B is C 1-20 alkyl.
  • the present disclosure provides a compound of formula (VII), or a pharmaceutically acceptable salt thereof, wherein R 7 is Mito; Mito is L is C 1-20 alkylene, C 2-20 alkenylene, L 1 -R C -L 2 , or amino acid; L 1 and L 2 are each independently absent or C 1 -C 10 alkylene; R C is –(CH 2 CH 2 O) q –, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently -CF 3 , Me, Cl, OMe, C(O)CH 3 , NO 2 , N(Me) 2 , COOH, F, Br, I, or OH; m at each occurrence is independently 0, 1, 2, 3, 4, or 5.
  • FIGS. 1A-1D show the effects of Mito-ortho-HNK analogs on the bacterial proliferation of E. faecalis.
  • FIG. 2A-2H show effects of Mito-ortho-HNK on the bacterial L-dopa consumptions with or without carbidopa.
  • E. faecalis was treated with the Mito-ortho-HNK as indicated in presence of 1 mM L-dopa alone (FIGS.2A-2D) or with additional 0.22 mM of carbidopa (FIGS. 2E-2H).
  • the effects of Mito-ortho-HNK on the proliferation in presence of L-dopa alone (FIG. 2A) or in presence of L-dopa and carbidopa combination FIG.
  • FIGS. 3A-3D show effects of Mito-PEG 5 -ATO on the bacterial L-dopa consumptions.
  • E. faecalis was treated with Mito-PEG 5 -ATO as indicated in presence of L- dopa (1 mM).
  • the effects of Mito-PEG 5 -ATO on the proliferation were monitored at OD 600 for 6 h and culture media were collected at indicated time points for L- dopa and dopamine measurements. High-performance liquid chromatography traces of representatives’ samples and standards are shown in panel (FIG.3B).
  • FIGS.3C and 3D show the effects of Mito- PEG 5 -ATO on L-dopa consumption and dopamine formation.
  • FIGS. 4A-4D show the effects of commonly used antibiotics and Mito-PEG- ATO analogs on the proliferation of gram-positive and gram-negative bacteria.
  • FIGS.5A-5D show effects of Mito-ortho-HNK and commonly used antibiotics on the bacterial membrane potential.
  • faecalis was treated with Mito- ortho-HNK (FIG. 5A) or commonly used antibiotics (FIG. 5B, chloramphenicol [Cam] and ampicillin [Amp]) as indicated for 1 h.
  • the effects on the membrane potential were measured by TMRM dye (50 nM), the fluorescence indicator, to determine the percentage change in TMRM fluorescence intensity between the control and treatments groups.
  • the lower levels of TMRM fluorescence resulting from treatment reflect the depolarization of mitochondrial membrane potential.
  • FIGS. 6A-6F show effects of Mito-ortho-HNK and antibiotics on ATP.
  • E. faecalis were treated with Mito-ortho-HNK (FIG. 6A) or commonly used antibiotics (chloramphenicol [Cam], FIG. 6B; ampicillin [Amp], FIG. 6C) as indicated.
  • FIGS.6A- 6C show the effects of Mito-ortho-HNK or antibiotics on E. faecalis proliferation shown as absorbance at OD600.
  • FIGS.7A-7D show effect of Mito-ortho-HNK on L-dopa/dopamine metabolism in vivo. Mice were orally treated with 150 mg/kg L-dopa-d3 with or without Mito-ortho- HNK for 2 h.
  • FIGS. 8A-8B illustrate gut microbial metabolism.
  • FIG. 8A shows the gut metabolism of L-dopa and m-tyramine, and
  • FIGS. 9A-9B illustrate chemical structures of drugs, MTDs and PEGylated MTDs, and L-dopa and analogs. Chemical structures of drugs, MTDs, and PEGylated MTDs are shown in (FIG.9A), and of L-dopa and analogs are shown in (FIG.9B). [0027] FIGS.10A-10B show effects of Mito-LND analogs and Mito-MGN analogs on the bacterial proliferation of E. faecalis. The effects of LND (FIG.
  • FIG. 11 shows the effects of common antibiotics and Mito-PEG-ATO analogs on the bacterial ATP level.
  • S. aureus cells were treated with common antibiotics ampicillin (Amp) and chloramphenicol (Cam), Mito-PEG 2 -ATO, and Mito-PEG 5 -ATO for 1 h. Intracellular ATP levels were measured using a luciferase-based assay.
  • FIG. 13A-13D show the effects of Mito 11 -APO on the bacterial L-dopa consumptions with carbidopa.
  • E. faecalis was treated with the Mito 11 -APO as indicated in presence of 1 mM L-dopa alone with additional 0.22 mM of carbidopa.
  • the effects of Mito 11 -APO on the proliferation in presence of L-dopa and carbidopa combination (FIG. 13A) were monitored at OD600 for 6 h and culture media were collected at indicated time points for L-dopa and dopamine measurements. High-performance liquid chromatography traces of representatives’ samples and standards are shown in panel (FIG.13B).
  • FIG. 15A-15D show the effects of Mito 10 -APO on the bacterial L-dopa consumptions with carbidopa.
  • E. faecalis was treated with the Mito 10 -APO as indicated in presence of 1 mM L-dopa alone with additional 0.22 mM of carbidopa.
  • the effects of Mito 10 -APO on the proliferation in presence of L-dopa and carbidopa combination (FIG. 15A) were monitored at OD600 for 6 h and culture media were collected at indicated time points for L-dopa and dopamine measurements. High-performance liquid chromatography traces of representatives’ samples and standards are shown in panel (FIG.15B).
  • FIG. 15C shows the effects of Mito 10 -APO on L-dopa consumption
  • FIG.15D dopamine formation
  • FIG. 16 shows the effects of Mito 2 -APO on the bacterial proliferation of E. faecalis.
  • FIGS.17A-17B show the effects of MitoQ analogs on the bacterial proliferation of E. faecalis.
  • FIGS.18A-18D show the effects of MitoQ and DM-MitoQ on the bacterial L- dopa consumptions with carbidopa. E. faecalis was treated with the MitoQ or DM-MitoQ as indicated in presence of 1 mM L-dopa alone with additional 0.22 mM of carbidopa.
  • FIG. 19 shows the structures of the Mito-APO, Mito-PEG-APO, and Mito-Q analogs.
  • FIG. 19 shows the structures of the Mito-APO, Mito-PEG-APO, and Mito-Q analogs.
  • the drawings illustrate only example embodiments and are therefore not to be considered limiting of the scope of the embodiments described herein, as other embodiments are within the scope of the disclosure. DETAILED DESCRIPTION OF THE INVENTION [0038] Before the present materials and methods are described, it is understood that this invention is not limited to the particular methodology, protocols, materials, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
  • alkyl as used herein, means a straight or branched chain saturated hydrocarbon.
  • the alkyl can be a ⁇ 1-4alkyl.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylene as used herein, means a divalent group derived from a straight or branched chain saturated hydrocarbon.
  • alkylene examples include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, and CH 2 CH(CH 3 )CH(CH 3 )CH 2 -.
  • alkene as used herein, means an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C 2 -C 12 -alkenyl, C 2 -C 10 - alkenyl, and C 2 -C 6 -alkenyl, respectively.
  • alkenylene as used herein, means a divalent group derived from a straight or branched alkene, which attaches to the parent molecule at two different carbon atoms.
  • aryl as used herein, means a carbocyclic aromatic group (e.g., phenyl or a bicyclic aryl).
  • aryl includes polycyclic ring systems having one or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls or cycloalkenyls.
  • a bicyclic aryl can be a phenyl fused to a cycloalkyl moiety.
  • aryl include naphthyl, dihydronaphthalenyl, tetrahydronaphthalenes, indanyl, or indenyl.
  • the aryl e.g., phenyl and bicyclic aryls
  • arylene as used herein, means a divalent group derived from an aryl as described herein, which attaches to the parent molecule at two different ring carbon atoms.
  • arylene includes, but are not limited to, phenylene, which is a divalent group derived from benzene and attaches to the parent molecule at two different ring carbon atoms (e.g., at 1,2-, 1,3-, or 1,4-positions).
  • cycloalkyl as used herein, means a monovalent group derived from an all-carbon ring system containing zero heteroatoms as ring atoms, and zero double bonds.
  • the all-carbon ring system can be a monocyclic, bicylic, or tricyclic ring system, and can be a fused ring system, a bridged ring system, or a spiro ring system, or combinations thereof.
  • cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and .
  • the cycloalkyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.
  • cycloalkylene as used herein, means a divalent group derived from an all-carbon ring system containing zero heteroatoms as ring atoms and zero double bonds, which attaches to the parent molecule at two different ring carbons atoms.
  • the all-carbon ring system can be a monocyclic, bicylic, or tricyclic ring system, and can be a fused ring system, a bridged ring system, or a spiro ring system.
  • Representative examples of cycloalkylene include, but are not limited to, those derived from C 3-10 rings, such as [0051]
  • the term “halogen” or “halo” means a chlorine, bromine, iodine, or fluorine atom.
  • C3alkyl is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl).
  • C 1 -C 4 or “C 1- 4 ,” the members of the group that follows may have any number of carbon atoms falling within the recited range.
  • substituents are described as being independently selected from a group, each substituent is selected independent of the other. Each substituent, therefore, may be identical to or different from the other substituent(s).
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, regioisomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and I double bond isomers, and (Z) and I conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • the compound disclosed herein may exist as a regioisomer or a mixture of regioisomers.
  • pharmaceutically acceptable salt thereof means a salt prepared by combining a compound of formula (III), (IV), (V), or (VI) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • the salts of the compounds of this invention are non-toxic “pharmaceutically acceptable salts”.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosul
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N, N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C 1 -C 6 ) halides (e.g.
  • isotopically labelled refers to compounds of formula (III), (IV), (V), or (VI) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically labelled compounds of formula (III), (IV), (V), or (VI), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically labeled compounds of formula (III), (IV), (V), or (VI) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically labeled reagents in place of the non-labeled reagent previously employed.
  • Site specific substitution of atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature can be regarded as a substituent of a compound of the present disclosure.
  • a sample of a compound having such an isotope as a substituent has at least 50% isotope incorporation at the labelled position(s).
  • the concentration of such isotopes may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • the term “effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired result, including a desired therapeutic result, such as modulation of microbial metabolism of levodopa, mitigation of microbial degradation of levodopa, improvement of bioavailability of levodopa in the brain, and treatment of Parkinson’s disease.
  • An effective amount of the compounds as disclosed herein may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the disclosed compounds to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the compounds as disclosed herein are reduced as compared with known compounds and are outweighed by the therapeutically beneficial effects.
  • Parkinson’s disease can be managed using levodopa; however, as Parkinson’s disease progresses, patients require increased doses of levodopa, which can cause undesirable side effects. Additionally, the oral bioavailability of levodopa decreases in Parkinson’s disease patients due to the increased metabolism of levodopa to dopamine by gut bacteria, Enterococcus faecalis, resulting in decreased neuronal uptake and dopamine formation. Parkinson’s disease patients have varying levels of these bacteria.
  • the present disclosure relates to methods of enhancing levodopa therapeutic efficacy in Parkinson’s disease.
  • the present method may involve inhibiting gut microbial metabolism of levodopa.
  • the present disclosure demonstrates that Mito-ortho-HNK, formed by modification of a naturally occurring molecule, honokiol, conjugated to a triphenylphosphonium moiety, mitigates the metabolism of levodopa—alone or combined with carbidopa—to dopamine.
  • Mito-ortho- HNK suppresses the growth of E. faecalis, decreases dopamine levels in the gut, and increases dopamine levels in the brain. Mitigating the gut bacterial metabolism of levodopa as shown here could enhance its efficacy.
  • L-dopa levodopa
  • PD Parkinson’s disease
  • a characteristic hallmark of PD is the loss of dopamine-producing neurons in the striatum.
  • Orally administered L-dopa crosses the blood–brain barrier and is metabolized to dopamine in the brain by the enzyme aromatic L-amino acid decarboxylase.
  • PD progresses, patients require increased doses of L-dopa, the side effects of which are dyskinesia and drug toxicity.
  • L-dopa induced dyskinesia is extremely debilitating and often requires withdrawal of L-dopa therapy.
  • L-dopa Using genome-mining techniques, E. faecalis was identified as the microbial species responsible for L-dopa metabolism. Investigators discovered that L-dopa is metabolized to dopamine by E. faecalis-derived tyrosine decarboxylases. Ex vivo human fecal suspensions from PD patients and healthy individuals were used to show that E. faecalis in gut microbiota is responsible for L-dopa metabolism.
  • L-dopa metabolism by gut commensal bacteria results in reduced therapeutic efficacy of L-dopa as well as increased m-tyramine generation from dopamine, which can have serious adverse effects.
  • Alpha-fluoromethyl amino acids known inhibitors of tyrosine decarboxylases, and the L- tyrosine analog (S)-alpha-fluoromethyltyrosine, both inhibit L-dopa decarboxylation in E. faecalis.
  • S L- tyrosine analog
  • the role of the microbiota–gut–brain axis in regulating dopaminergic signaling is gaining increased attention.
  • Bacterial tyrosine decarboxylases is present in all but three of 655 E.
  • carbidopa an inhibitor of extracerebral aromatic L-amino acid decarboxylase, prevents its peripheral metabolism to dopamine.
  • carbidopa is not an effective inhibitor of the enzyme tyrosine decarboxylases; it is 200-fold less active toward E. faecalis tyrosine decarboxylases relative to human dopa decarboxylase and is unable to prevent gut bacterial L-dopa metabolism.
  • Antimicrobial therapy has been suggested as a nontoxic, highly effective approach to mitigating the gut metabolism of L-dopa to dopamine and enhancing the uptake and metabolism of L-dopa into the brain in murine models of PD.
  • Cationic compounds can interact with bacterial membranes and inhibit bacterial growth, including triphenylphosphonium cation (TPP + )-based mitochondria-targeted compounds that have been shown to be effective antimicrobial agents.
  • TPP + triphenylphosphonium cation
  • the present disclosure provides a method of modulating microbial metabolism of levodopa in gut of a subject in need thereof, the method comprising administering to the subject levodopa and an effective amount of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, as described herein.
  • the present disclosure provides a method of mitigating microbial degradation of levodopa in gut of a subject in need thereof, the method comprising administering to the subject levodopa and an effective amount of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, as described herein.
  • the present disclosure provides a method of improving bioavailability of levodopa in brain of a subject in need thereof, the method comprising administering to the subject levodopa and an effective amount of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, as described herein.
  • the present disclosure provides a method of treating Parkinson’s disease in a subject in need thereof, the methods comprise administering to the subject levodopa and an effective amount of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, as described herein.
  • the foregoing methods include administration of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof,
  • the uptake of levodopa in the brain of the subject is increased and/or formation of dopamine in the brain of the subject is increased.
  • the present methods may include an increase in the uptake of levodopa in the brain of the subject, such as an increase of levodopa uptake of about 5%, about 10%, about 20%, about 50%, about 100%, about 200%, or about 500%.
  • the present methods may include an increase of the formation of dopamine in the brain of the subject, such as an increase of dopamine formation of about 5%, about 10%, about 20%, about 50%, about 100%, about 200%, or about 500%.
  • the microbial metabolism of levodopa to dopamine in the gut of the subject is decreased.
  • the present methods may include a decrease of levodopa metabolism of about 5%, about 10%, about 20%, about 50%, or about 80% in the gut of the subject.
  • the compound used for the present methods is a compound of formula (III) or (IV), or a pharmaceutically acceptable salt thereof.
  • the compound has formula (III) or (IV), in which one of R 3 and R 4 in formula (III) or (IV) is Mito and the other is H.
  • the compound has formula (III), in which R 3 is Mito and R 4 is H.
  • the compound has formula (III), in which R 3 is H and R 4 is Mito. In some embodiments, the compound has formula (IV), in which R 3 is Mito and R 4 is H. [0078] In some embodiments, the compound used for the present methods is a compound of formula (V) or (VI), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound has formula (V) or (VI), in which each of R 5 and R 6 in formula (V) and (VI), respectively, is Mito. [0079] In some embodiments, the compound used for the present methods is a compound of formula (VII) or (VIII), or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (VII), or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (VIII), or a pharmaceutically acceptable salt thereof, in which L A is C(O), L B is O, f is 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 and R 8 is H.
  • the compound used for the present methods is a compound of formula (IX) or (X), or a pharmaceutically acceptable salt thereof.
  • the compound has formula (IX).
  • the compound has formula (X).
  • the compound has formula (IX) or (X), in which u is 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • X in the compounds as described herein is halogen, trifluoroacetate, or acetate.
  • X can be Br – or trifluoroacetate.
  • L in the compounds as described herein is C 1-20 alkylene.
  • L can be –(CH 2 ) 4 –, –(CH 2 ) 6 –, –(CH 2 ) 8 –, –(CH 2 ) 10 –, or –(CH 2 ) 12 –.
  • L is –(CH 2 ) 10 –.
  • L in the compounds as described herein is L 1 -R C -L 2 , and R C is —(CH 2 CH 2 O) q –.
  • R C is –(CH 2 CH 2 O) q –, in which q is 1, 2, 3, 4, 5, 6, 7, or 8.
  • L is –(CH 2 CH 2 O) q –CH 2 CH 2 –, in which q is 1, 2, 3, 4, or 5.
  • L is –(CH 2 CH 2 O) 3 –CH 2 CH 2 – or –(CH 2 CH 2 O) 4 –CH 2 CH 2 –.
  • Examples of compounds as described herein include those disclosed in WO 2016/201188 A1, WO 2019/136154 A1, WO 2021/081500 A1, and WO 2010/126719 A1, which are incorporated herein by reference in their entireties. [0085] In some embodiments, the compound is selected from the group consisting of
  • the present methods may include simultaneous, separate, or sequential administration of levodopa and a compound as described herein.
  • levodopa and a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof can be administrated to a subject in need thereof simultaneously, separately, or sequentially.
  • the present methods may include administration of levodopa and a compound as described herein in a combination with an additional active agent.
  • the additional active agent can include, for example, known medications or therapies used in the management and treatment of Parkinson disease.
  • the addition active agent may modulate the gut and/or peripheral metabolism of levodopa.
  • carbidopa is currently used with L-dopa in the treatment of PD symptoms.
  • Carbidopa inhibits the peripheral metabolism of L-dopa by acting as a substrate inhibitor of peripheral amino carboxylases.
  • a combination of the present compounds and carbidopa may inhibit both the microbial metabolism and the peripheral metabolism of L-dopa.
  • the present methods include administrating levodopa, the compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, to the subject in a combination with carbidopa.
  • the present disclosure provides a pharmaceutical composition
  • the pharmaceutical compositions may take any physical form which is pharmaceutically acceptable; illustratively, they can be orally administered pharmaceutical compositions. Such pharmaceutical compositions may contain a therapeutically effective amount of levodopa and an effective amount of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, as described herein, which is related to the dose of the compound to be administered. [0089] The compositions may contain from about 0.5% to about 50% of the compound in total, depending on the desired doses and the type of composition to be used.
  • the pharmaceutical composition includes a compound as described herein in a range from about 0.1 to about 2000 mg, such as from about 0.5 to 500 mg or from about 1 to about 100 mg.
  • the pharmaceutical composition may be administered to provide the compound at a daily dose of about 0.01 mg/kg to about 1000 mg/kg body weight, such as about 0.01 mg/kg to about 100 mg/kg, about 0.1 mg/kg to about 1000 mg/kg, about 0.1 to about 500 mg/kg, about 0.1 to about 100 mg/kg, or about 50 to about 100 mg/kg body weight.
  • the concentration of the compound at the site of action may be within a concentration range bounded by end- points selected from 0.001 ⁇ M, 0.005 ⁇ M, 0.01 ⁇ M, 0.5 ⁇ M, 0.1 ⁇ M, 1.0 ⁇ M, 10 ⁇ M, and 100 ⁇ M (e.g., 0.1 ⁇ M – 1.0 ⁇ M).
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Examples of suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E.W. Martin.
  • Suitable pharmaceutically acceptable carriers include, but are not limited to, for example, suitable diluents, vehicles, excipients, preservatives, solubilizers, emulsifiers, liposomes, or nanoparticles, among others. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of nonaqueous solutions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include isotonic solutions, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the formulation should be selected according to the mode of administration.
  • the compositions may include a pharmaceutical carrier, excipient, or diluent, which are nontoxic to the subject being exposed thereto at the dosages and concentrations employed.
  • Examples of pharmaceutical carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN brand surfactant, polyethylene glycol (PEG), and PLURONICSTM surfactant.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • proteins
  • Oral administration is an illustrative route of administering the compounds employed in the compositions and methods disclosed herein.
  • Other illustrative routes of administration include transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, intrathecal, intracerebral, or intrarectal routes.
  • the route of administration may be varied in any way, limited by the physical properties of the compounds being employed and the convenience of the subject and the caregiver.
  • Suitable formulations include those that are suitable for more than one route of administration.
  • the formulation can be one that is suitable for both oral and intravenous administration.
  • suitable formulations include those that are suitable for only one route of administration as well as those that are suitable for one or more routes of administration, but not suitable for one or more other routes of administration.
  • the formulation can be one that is suitable for oral, topical, transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, and/or intrathecal administration but not suitable for intracerebral administration.
  • the inert ingredients and manner of formulation of the pharmaceutical compositions may be selected from conventional technologies. The usual methods of formulation used in pharmaceutical science may be used here.
  • compositions include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches, and suspensions.
  • Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules.
  • the usual diluents include inert powdered substances (such as starches), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol and sucrose), grain flours, and similar edible powders, but any suitable capsule formulation can be used.
  • Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants, and disintegrators (in addition to the compounds). Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives can also be used. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, and the like).
  • Natural and synthetic gums can also be used, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.
  • Tablets can be coated with sugar, e.g., as a flavor enhancer and sealant.
  • the compounds also may be formulated as chewable tablets, by using large amounts of pleasant-tasting substances, such as mannitol, in the formulation.
  • Instantly dissolving tablet-like formulations can also be employed, for example, to assure that the patient consumes the dosage form and to avoid the difficulty that some patients experience in swallowing solid objects.
  • a lubricant can be used in the tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils.
  • Tablets can also contain disintegrators. Disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins, and gums.
  • compositions can be formulated as enteric formulations, for example, to protect the active ingredient from the strongly acid contents of the stomach.
  • enteric formulations can be created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments and soluble in basic environments.
  • Transdermal patches can also be used to deliver the compounds.
  • Transdermal patches can include a resinous composition in which the compound will dissolve or partially dissolve; and a film which protects the composition, and which holds the resinous composition in contact with the skin.
  • Other, more complicated patch compositions can also be used, such as those having a membrane pierced with a plurality of pores through which the compound is pumped by osmotic action.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis.
  • Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the pharmaceutical compositions are in some embodiments applied as a topical ointment or cream.
  • the compound When formulated in an ointment, the compound may be employed with either a paraffinic or a water-miscible ointment base.
  • the compound may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • Pharmaceutical compositions adapted for topical administration to the eye include eye drops where the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • the composition can be prepared with materials (e.g., actives excipients, carriers (such as cyclodextrins), diluents, etc.) having properties (e.g., purity) that render the formulation suitable for administration to humans or non-human subjects.
  • the composition is suitable for use in humans.
  • the composition is prepared with materials having purity and/or other properties that render it suitable for administration to non-human subjects, but not suitable for administration to humans.
  • Each dosage unit may contain the dose of a given compound, for example, a daily dose, or each dosage unit may contain a fraction of the daily dose, such as one-half or one-third of the dose.
  • each compound to be contained in each dosage unit can depend, in part, on the identity of the particular compound chosen for the therapy and other factors, such as the indication for which it is given.
  • the pharmaceutical compositions disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing well known procedures.
  • the composition may include a single compound or a combination of compounds as described herein for administration. For example, two or more of the compounds described herein may be included in the composition.
  • the composition may include solvate forms of the compounds or salts, esters, and/or amides, thereof. Solvate forms may include ethanol solvates, hydrates, and the like.
  • the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered with additional therapeutic agents.
  • the additional therapeutic agent may include, for example, one or more known agent for treating Parkinson’s disease.
  • one or more additional therapeutic agents are administered with the disclosed compounds or with pharmaceutical compositions comprising the disclosed compounds, where the additional therapeutic agent is administered prior to, concurrently with, or after administering the disclosed compounds or the pharmaceutical compositions comprising the disclosed compounds.
  • the disclosed pharmaceutical compositions are formulated to comprise the disclosed compounds and further to comprise the one or more additional therapeutic agents.
  • the compound used for the present pharmaceutical compositions is a compound of formula (III) or (IV), or a pharmaceutically acceptable salt thereof.
  • the compound has formula (III) or (IV), in which one of R 3 and R 4 in formula (III) or (IV) is Mito and the other is H. In some embodiments, the compound has formula (III), in which R 3 is Mito and R 4 is H. In some embodiments, the compound has formula (III), in which R 3 is H and R 4 is Mito. In some embodiments, the compound has formula (IV), in which R 3 is Mito and R 4 is H. [00111] In some embodiments, the compound used for the present pharmaceutical compositions is a compound of formula (V) or (VI), or a pharmaceutically acceptable salt thereof.
  • the compound has formula (V) or (VI), in which each of R 5 and R 6 in formula (V) and (VI), respectively, is Mito.
  • the compound used for the present pharmaceutical compositions is a compound of formula (VII) or (VIII), or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (VII), or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (VIII), or a pharmaceutically acceptable salt thereof, in which L A is C(O), L B is O, f is 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 and R 8 is H.
  • the compound used for the present pharmaceutical compositions is a compound of formula (IX) or (X), or a pharmaceutically acceptable salt thereof.
  • the compound has formula (IX).
  • the compound has formula (X).
  • the compound has formula (IX) or (X), in which u is 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the pharmaceutical composition includes a compound as described herein, in which X is halogen, trifluoroacetate, or acetate.
  • the pharmaceutical composition includes a compound as described herein, in which L is C 1-20 alkylene.
  • the pharmaceutical composition includes a compound as described herein, in which L is L 1 -R C -L 2 , and R C is — (CH 2 CH 2 O) q –. [00116] In some embodiments, the pharmaceutical composition includes a compound as described herein, which is selected from the group consisting of
  • the pharmaceutical composition further comprises an additional active agent, such as carbidopa.
  • the present disclosure provides a compound of formula (III-a) or (IV-a), or a pharmaceutically acceptable salt thereof, w ere n one of R 3 and R 4 is Mito, the other is –(CH 2 CH 2 O) v –R A ; v is 1-20; R A is H or C 1-4 alkyl; Mito is L is C 1-20 alkylene, C 2-20 alkenylene, L 1 -R C -L 2 , or amino acid; L 1 and L 2 are each independently absent or C 1 -C 10 alkylene; R C is –(CH 2 CH 2 O) q –, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently -CF 3 , Me, Cl, OMe, C(O)
  • the compound has formula (III-a), in which R 3 is Mito and R 4 is–(CH 2 CH 2 O) v –R A . In some embodiments, the compound has formula (III-a), in which R 3 is –(CH 2 CH 2 O) v –R A and R 4 is Mito. In some embodiments, the compound has formula (IV-a), in which R 3 is Mito and R 4 is–(CH 2 CH 2 O) v –R A . In some embodiments, the compound has formula (III-a) or (IV-a), in which v is 1, 2, 3, 4, or 5.
  • the compound has formula (III-a) or (IV-a), in which v is 1, 2, 3, 4, or 5 and R A is methyl.
  • Examples of compounds of formula (III-a) and (IV-a) include: o a p a aceu ca y accep a e sa e eo .
  • the present disclosure provides a compound of formula (V-a) or (VI-a), or a pharmaceutically acceptable salt thereof, wherein each of R 5 and R 6 is –(CH 2 CH 2 O) w –R A or R B ; w is 1-20; Z is NH or O R A is H or C 1-4 alkyl; R B is C 1-20 alkyl.
  • the compound has formula (V-a) or (VI-a) , in which each of R 5 and R 6 is –(CH 2 CH 2 O) w –R A and w is 1, 2, 3, 4, or 5.
  • the compound has formula (V-a), in which R 5 is –(CH 2 CH 2 O) w –R A , w is 1, 2, 3, 4, or 5, and R A is methyl.
  • the compound has formula (V-a), in which R 5 is R B .
  • R B is C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , or C11 alkyl.
  • the compound has formula (VI-a), in which Z is NH, R 6 is –(CH 2 CH 2 O) w –R A , and w is 1, 2, 3, 4, or 5.
  • the compound has formula (VI-a), in which Z is O, R 6 is –(CH 2 CH 2 O) w –R A , and w is 1, 2, 3, 4, or 5. In some embodiments, R A is methyl.
  • Examples of compounds of formula (V-a) and (VI-a) include: Cl or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of formula (VII), or a pharmaceutically acceptable salt thereof, wherein R 7 is Mito; Mito is L is C 1-20 alkylene, C 2-20 alkenylene, L 1 -R C -L 2 , or amino acid; L 1 and L 2 are each independently absent or C 1 -C 10 alkylene; R C is –(CH 2 CH 2 O) q –, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently -CF 3 , Me, Cl, OMe, C(O)CH 3 , NO 2 , N(Me) 2 , COOH, F, Br, I, or OH; m at each occurrence is independently 0, 1, 2, 3, 4, or 5.
  • the compound has formula (VII), in which L is L 1 -R C -L 2 , and R C is –(CH 2 CH 2 O) q –.
  • R C is –(CH 2 CH 2 O) q –, in which q is 1, 2, 3, 4, 5, 6, 7, or 8.
  • L is –(CH 2 CH 2 O) q –CH 2 CH 2 –, in which q is 1, 2, 3, 4, or 5.
  • L is –(CH 2 CH 2 O) 3 –CH 2 CH 2 – or –(CH 2 CH 2 O) 4 – CH 2 CH 2 –.
  • the compound has formula (VII), in which L is C 1 - 20 alkylene, such as –(CH 2 ) 4 –, –(CH 2 ) 6 –, –(CH 2 ) 8 –, –(CH 2 ) 10 –, or –(CH 2 ) 12 –. In some embodiments, L is –(CH 2 ) 10 –.
  • the compound has formula (VII), in which X is halogen, trifluoroacetate, or acetate. For example, X can be Br – or trifluoroacetate.
  • Examples of compounds of formula (VII) include: or a pharmaceutically acceptable salt thereof.
  • kits comprising an effective amount of levodopa, and an effective amount of a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, as described herein and instructional material.
  • the term "instructional material” refers to a publication, a recording, a diagram, or any other medium of expression which is used to communicate the usefulness of the present pharmaceutical composition for one of the purposes set forth herein in a human.
  • the instructional material can also, for example, describe an appropriate dose of the present pharmaceutical composition.
  • the instructional material of the present kit can, for example, be affixed to a container which contains a pharmaceutical composition as disclosed herein or be shipped together with a container which contains the pharmaceutical composition. Alternatively, the instructional material can be shipped separately from the container with the intention that the instructional material and the pharmaceutical composition be used cooperatively by the recipient.
  • the present kit may include instruction for simultaneous, separate, or sequential administration of levodopa and a compound as described herein. For example, levodopa and a compound of formula (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, as described herein, can be administrated to a subject in need thereof simultaneously, separately, or sequentially.
  • Mito-ortho-HNK and Mito-PEG 4 -HNK and analogs inhibit E. faecalis proliferation
  • Mito-ortho-HNK and PEGylated mitochondria-targeted honokiol are nearly 20 times more effective than unmodified honokiol (HNK) in inhibiting E. faecalis proliferation (FIGS.1A and 1C).
  • Mito-ortho-HNK analogs delayed the proliferation of E. faecalis.
  • Mito-PEG 5 -ATO inhibits L-dopa metabolism to dopamine by E. faecalis
  • FIG. 3A PEGylated mitochondria-targeted atovaquone (Mito- PEG 5 -ATO) dose-dependently inhibited E. faecalis proliferation in presence of L-dopa (1 mM). Samples isolated at various time points were analyzed by high-performance liquid chromatography (FIG. 3B).
  • Mito-PEG 5 -ATO dose dependently inhibited L-dopa consumption (FIG.3C) by E. faecalis and the formation of dopamine (FIG.3C).
  • Samples collected at the 2.5 h time point showed that treatment with 2.5 ⁇ M Mito-PEG 5 -ATO caused a 50% inhibition in L-dopa consumption and dopamine formation (FIGS. 3C and 3D).
  • Antimicrobial effects of MTDs on gut bacteria [00144] To determine the impact of MTDs and related controls on bacterial growth, the minimal inhibitory concentration values were measured by micro broth-dilution assay. Minimal inhibitory concentration is the lowest concentration of an antibiotic that fully inhibits the growth of a bacterial strain.
  • FIGS.4A-4D The effects of commonly used antibiotics and Mito-PEG-ATO analogs on the proliferation of E. faecalis are shown in FIGS.4A-4D. Results show that chloramphenicol and ampicillin dose-dependently inhibited E. faecalis proliferation. However, Mito-PEG- ATO and analogs exhibited a time lag depending on the concentration. At 2.5 ⁇ M concentration, E. faecalis proliferation was maximally inhibited for 2 h, and then it started to proliferate and reached a similar level of confluence as control.
  • FIG.5A shows that Mito-ortho-HNK dose-dependently decreased tetramethylrhodamine (TMRM) fluorescence due to depolarization of bacterial membrane potential.
  • TMRM tetramethylrhodamine
  • ATP levels started to decrease due to increased utilization of ATP (FIGS.6D-6F).
  • Mito-ortho- HNK commonly used antibiotics chloramphenicol and ampicillin did not increase ATP levels in E. faecalis compared with the control.
  • ATP levels decreased below the control levels, despite a decreased rate of proliferation.
  • L-dopa-d3 levodopa-d3
  • a stable form of L-dopa with a deuterium substituted aromatic ring that crosses the blood–brain barrier (FIGS.7A and 9B).
  • the labeling with deuterium in L-dopa-d3 allowed us to track the distribution and metabolism of L-dopa-d3 to dopamine-d3 in the brain and gut (FIGS. 7A-7D).
  • mice treated with L-dopa-d3 (150 mg/kg) or L-dopa-d3 (150 mg/kg) + Mito-ortho-HNK (10 mg/kg) by oral gavage show L-dopa metabolism and dopamine-d3 formation by gut microbiome from gut-homogenized samples (FIGS.7A and 7B).
  • Mito-ortho-HNK inhibited dopamine-d3 formation (FIG.7B) and L-dopa-d3 consumption (FIG. 7B) as compared with the control mouse in gut homogenized samples.
  • the antibiotics ampicillin and chloramphenicol inhibit both gram-negative and gram-positive bacteria
  • Mito-PEG-HNK, Mito-PEG-ATO, and Mito-LND show selectivity.
  • the intracellular ATP was measured in S. aureus cells in the presence of Mito- PEG-ATO analogs and the common antibiotics, ampicillin, and chloramphenicol.
  • Mito-PEG 5 -ATO was nearly 50 times more potent than ampicillin and nearly 500 times more potent than chloramphenicol in inhibiting intracellular ATP levels and bioenergetics.
  • Tetracycline antibiotics such as doxycycline and minocycline were reported to be effective in mitigating the progression of neuronal dysfunction in mice models of PD.
  • Neuroprotective mechanisms of antibiotics are distinctly different from their antibacterial mechanisms.
  • Conventional antibiotics inhibit the growth of bacteria through inhibition of bacterial proteins, cell membranes, cell walls, or nucleic acid syntheses.
  • mitochondria-targeted agents exert cytostatic and not cytotoxic effects in E. faecalis.
  • E. faecalis isolates displayed a high level of resistance to several traditional antibiotics including to tetracycline antibiotics.
  • Mitochondria-targeted drugs may have some advantages over the traditional antimicrobials. Mitochondria-targeted drugs are more potent than the conventional antibiotics in inhibiting the proliferation of E. faecalis (Table 1, FIGS. 4A-4D). Other commensal species expected to be present in the gut may be further examined. Nonetheless, the results here suggest that the dose-dependence of this drug will likely differ for different species and different locations within the gut. However, the present findings indicate that the impact of mitochondria-targeted drugs (e.g., Mito-ortho-HNK and Mito- PEG 5 -ATO) is temporary and may provide a window of opportunity to enhance the therapeutic efficacy of L-dopa.
  • mitochondria-targeted drugs e.g., Mito-ortho-HNK and Mito- PEG 5 -ATO
  • Mito-ortho-HNK at 4 micromolar levels caused a substantial decrease in membrane potential in E. faecalis (FIG.5A). At this concentration, the proliferation of E. faecalis was inhibited (>90%) for 2–3 h (FIG. 5B). The SYTOX assay indicated that Mito-ortho-HNK was not cytotoxic at this concentration (FIG. 5B). Previously, it has been reported that bacterial cell division is dependent on membrane potential. The antibacterial effect of Mito-ortho-HNK is mechanistically different from those of chloramphenicol and ampicillin. Both chloramphenicol and ampicillin inhibited E. faecalis proliferation but did not affect its membrane potential (FIG.
  • Mito-HNK The lack of in vivo toxicity of Mito-HNK was previously reported in Pan, J. et al. (Mitochondria-targeted honokiol confers a striking inhibitory effect on lung cancer via inhibiting complex I activity. iScience 3, 192–207 (2016)).
  • the potential toxicity and neurological changes induced by Mito-HNK were assessed in an eight-week toxicology study in A/J mice. Mice were treated with vehicle control and with various doses of Mito- HNK (7.5, 37.5, and 75 ⁇ mol/kg, which represent 2 ⁇ , 10 ⁇ , and 20 ⁇ the therapeutically effective dose of 3.75 ⁇ mol/kg in the lung cancer mouse model, respectively), given via oral gavage five days per week for eight weeks.
  • Mito-HNK did not affect the motor function monitored in a rotarod assay. 18 Overall, Mito-HNK did not show any indications of toxicity at a dose that is 20- fold higher than the maximally tolerated dose. [00165] PEGylation decreases the hydrophobicity of MTDs, and nearly all MTDs and Mito-PEG analogs have similar alkyl side-chain lengths but substantially different hydrophobicities (log P [octanol partition coefficients]).
  • the calculated log P values for atovaquone, HNK, lonidamine, Mito 10 -ATO, Mito-ortho-HNK, Mito-lonidamine, Mito- PEG 5 -ATO, Mito-PEG4-HNK, and Mito-PEG4-APO are 5.1, 5.2, 4.5, 12.8, 13.0, 9.3, 9.2, 9.5, and 5.4, respectively. This approach enables further development to vary drug hydrophobicity and enhance the antimicrobial effects of MTDs.
  • MTDs e.g., Mito-apocynin and Mito-quinone
  • MTDs prevent hyposmia and loss of motor function in LRRK2 PD mice, and they inhibit MPTP (1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neurotoxicity in a PD mouse model.
  • a combination of L-dopa and carbidopa is the treatment of choice for managing PD symptoms.
  • Carbidopa does not prevent gut metabolism of L-dopa but does inhibit the peripheral metabolism of L-dopa by acting as a substrate inhibitor of peripheral amino carboxylases.
  • MTDs could enhance the efficacy of L-dopa/carbidopa therapy by directly reversing the gut bacteria metabolism of L-dopa. Thus, it is conceivable that a combination of MTD/L-dopa/carbidopa therapy may inhibit both the microbial metabolism and the peripheral metabolism of L-dopa.
  • Methods [00169] Syntheses of MTDs [00170] MTDs (e.g., Mito-ortho-HNK) were prepared by conjugating the mitochondria- targeting TPP + moiety to the corresponding parent molecule via alkyl linkers of different natures and lengths (FIG. 9A).
  • faecalis cells were diluted 1:100 into fresh tryptic soy broth medium. Then, they were grown at 37°C in flasks on a rotating shaker at 250 rpm to reach the exponential growth phase (optical density at 600 nm [OD 600 ] of 0.2– 0.5) before use in the in vitro assays. For all proliferation assays, cells were diluted to the final OD 600 of 0.1 with indicated treatments in a 96-well plate. Cell proliferation, which was represented as absorbance at 600 nm, was acquired in real time every 3 min for 6 h using a plate reader (BMG Labtech, Inc., Ortenberg, Germany) equipped with an atmosphere controller set at 37°C, 100% air.
  • a plate reader BMG Labtech, Inc., Ortenberg, Germany
  • E. faecalis cells in the exponential growth phase were diluted to the final OD600 at 0.1. Then, they were treated in presence of L-dopa (1 mM) alone or in combination with carbidopa (0.22 mM) in the same manner as described for Mito-ortho- HNK. At the indicated time points (1–6 h), samples (1 ml of media) were collected by centrifugation at 2500 g ⁇ 5 min at 4°C and stored at ⁇ 80°C before performing lyophilization.
  • LC-MS experiments [00177] L-Dopa and its metabolites were separated and monitored by LC-MS using an Agilent 1200 apparatus equipped with an ultraviolet-visible absorption and mass spectrometry detector (single quadrupole). Typically, 2 ⁇ L of a sample was injected on an Agilent Poroshell column (120 HILIC-Z, PEEK, 100 mm ⁇ 2.1 mm, 2.7 ⁇ m, 25°C). The absorption traces were collected at 280 nm.
  • L-Dopa-d3 and dopamine-d3 were separated and monitored by liquid chromatography–mass spectrometry–single ion monitoring (LC-MS-SIM) using an Agilent 1200 apparatus equipped with an ultraviolet-visible absorption and MS detector (single quadrupole).
  • LC-MS-SIM liquid chromatography–mass spectrometry–single ion monitoring
  • Agilent 1200 apparatus equipped with an ultraviolet-visible absorption and MS detector (single quadrupole).
  • 2 ⁇ L of a sample was injected on an Agilent Poroshell column (120 HILIC-Z, PEEK, 100 mm ⁇ 2.1 mm, 2.7 ⁇ m, 25°C) equilibrated with 100% ammonium formate (10 mM, pH 3.0 containing acetonitrile/water, 9/1,).
  • MS-SIM mass spectrometry–single ion monitoring
  • Bacterial membrane potential and cytotoxicity assay [00181] The effects of MTDs on bacterial membrane potential were determined using the fluorescent dye TMRM. Briefly, bacteria in the exponential growth phase (OD 600 of 0.4) were treated as indicated for the MTDs or commonly used antibiotics in a black, clear- bottom 96-well plate; then, an aliquot of TMRM was added at a final concentration of 50 nM for 20 min. After incubation with TMRM, the plate was centrifuged twice at 2500 g for 5 min and washed with phosphate buffered saline. Fluorescence was monitored at an excitation of 544 nm and emission of 590 nm using a plate reader (BMG Labtech, Inc.).
  • Fluorescence intensities from the dead cells in the 96-well plate were acquired in real time every 5 min for 3 h using a plate reader (BMG Labtech, Inc.) equipped with an atmosphere controller set at 37°C, 100% air using a fluorescence detection with 485 nm excitation and 535 nm emission. Data are represented as mean fluorescent intensity.
  • Intracellular ATP levels [00184] A luciferase-based assay was used to measure intracellular adenosine triphosphate (ATP) levels according to the manufacturer’s instructions (Sigma Aldrich, St. Louis, MO, Cat# FLLAA). Briefly, a mixture containing luciferase and luciferin (Cat# FLAAM) was added to cell lysates.
  • mice were sacrificed, and the brain tissue and gut tissue (including stomachs and intestines) were harvested, snap frozen in liquid nitrogen, and then stored at ⁇ 80°C before extraction.
  • the protocol for extracting L-dopa and dopamine is the same as described previously.
  • tissue weight was obtained, it was transferred to a homogenization tube containing 1 ml of ice-cold methanol.
  • the tissue homogenization and extraction were performed using an Omni Bead Ruptor 24 homogenizer (Omni International, Kennesaw, GA). The homogenate was centrifuged at 16,000 ⁇ g for 10 min 4°C; then, the supernatant was collected and transferred to a new 1.5 ml microcentrifuge tube for lyophilization.
  • Mito-PEG 4 -HNK was prepared in two steps, by reacting the appropriate PEGylated dibromoalcane with honokiol in the presence of potassium carbonate in DMF. The addition of triphenylphosphine on the bromopegylated honokiol (HNK-PEG 4 -Br) led to Mito-PEG4-HNK. In addition, the Mito-HNK was pegylated by using similar procedure in the presence of bromo-2,5,8,11-tetraoxatridecane and led to Mito-HNK-PEGOMe (Scheme 2).
  • Mito-HNK-PEGOMe is obtained as a white solid (145 mg, 61 % yield).
  • HRMS calculated for Mito-HNK-PEGOMe C55H70O6P + [M] + 857.4905, found, 857.4899.
  • Mito-PEG 4 -LON The pegylated mitochondria-targeted analog of lonidamine (Mito-PEG-LON) was prepared in three steps, by reacting the freshly prepared acyl chloride of lonidamine with 2- ⁇ 2-[2-(2-bromoethoxy)ethoxy]ethoxy ⁇ ethanol (Br-PEG4-OH) in the presence of TEA in CH 2 Cl 2 . Addition of triphenylphosphine on the bromopegylated lonidamine (PEG-LON-Br) led to Mito-PEG-LON in 40% yield.
  • PEG-LON pegylated lonidamine
  • MeO-PEG4-NH 2 2, 5, 8, 11-tetraoxatridecan-13-amine
  • Scheme 5 Synthesis of Mito-PEG-LON and PEG-LON. Reagents and conditions: I, (COCl) 2 , CH 2 Cl 2 , DMF, reflux, 2h., qt. Br-PEG4-OH, TEA, CH 2 Cl 2 51%; iii, triphenylphosphine, CH 3 CN, reflux, 18h, 40%.
  • MeO-PEG4-NH 2 (0.13 g, 1 mmol) and triethylamine (284 ⁇ L, 2 mmol) were added to a solution of acyl chloride in CH 2 Cl 2 (10 mL), and the reaction mixture was stirred for 12 h at room temperature and then washed with water (30 mL). The organic layer was dried over Na 2 SO 4 and the solvent distilled under reduced pressure. Purification of the crude product by flash chromatography on a silica gel (CH 2 Cl 2 /EtOH, 95:05) afforded LON-PEG (0.14 g, 46%).
  • the pegylated mitochondria-targeted analog of apocynine (Mito-PEG-APO) was prepared in two steps, by reacting the 1,11-Dibromo-3,6,9-trioxaundecane (Br-PEG- Br) with apocynine in the presence of potassium carbonate in DMF. Addition of triphenylphosphine on the bromopegylated apocynine (APO-PEG-Br) led to the Mito- PEG-APO.
  • non-pegylated mitochondria targeted apocynine (Mito 10 -APO) was prepared by using similar procedure in the presence of (10-bromodecyl)- triphenylphosphonium bromide (Mito-Br).
  • Scheme 6 Synthesis of Mito-PEG-APO and Mito 10 -APO. Reagents and conditions: i, Br-PEGn-Br, K 2 CO 3 , DMF, 45°C, 18h, 47%; ii, triphenylphosphine, CH 3 CN, reflux, 18h, 59%; iii, Mito-Br, K 2 CO 3 , DMF, 80°C, 18h, 43%.
  • FIGS. 12, 14 and 16 show the effects of Mito-APO analogs on the bacterial proliferation of E. faecalis.
  • FIGS. 13A-13D show effects of Mito 11 -APO on the bacterial L-dopa consumptions with or without carbidopa. E.
  • FIGS. 15A-15D show the effects of Mito 10 -APO on the bacterial L-dopa consumptions with or without carbidopa. E. faecalis was treated with the Mito 10 -APO as indicated in presence of 1 mM L-dopa alone with additional 0.22 mM of carbidopa.
  • FIGS.17A-17B show the effects of MitoQ analogs on the bacterial proliferation of E. faecalis.
  • DM-MitoQ was prepared in a two-step synthesis (Scheme 7). After the reduction of MitoQ using sodium borohydride, reduced MitoQ was dimethylated by methyl iodide in the presence of potassium carbonate in DMF, leading to DM-MitoQ.
  • Scheme 7 Synth esis of DM-MitoQ. Reagents and conditions: i, NaBH4, MeOH, 30 min.; ii, MeI, K 2 CO 3 , DMF, 40°C, 12h, 30%.

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Abstract

La présente divulgation concerne des procédés d'amélioration de l'efficacité thérapeutique de la lévodopa aux fins du traitement de la maladie de Parkinson. Les présents procédés peuvent comprendre l'administration de composés présentant une fraction triphénylphosphonium. Avantageusement, le présent procédé peut atténuer le métabolisme microbien de la lévodopa en dopamine dans l'intestin, améliorer la biodisponibilité de la lévodopa dans le cerveau, et accroître les niveaux de dopamine dans le cerveau.
PCT/US2024/054451 2023-11-03 2024-11-04 Procédés d'amélioration de l'efficacité thérapeutique de la lévodopa Pending WO2025097160A1 (fr)

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