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WO2025059405A1 - Compositions destinées à être utilisées dans une méthode de traitement d'une maladie ou d'une affection du motoneurone associée à un variant pathogène spg11 - Google Patents

Compositions destinées à être utilisées dans une méthode de traitement d'une maladie ou d'une affection du motoneurone associée à un variant pathogène spg11 Download PDF

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WO2025059405A1
WO2025059405A1 PCT/US2024/046533 US2024046533W WO2025059405A1 WO 2025059405 A1 WO2025059405 A1 WO 2025059405A1 US 2024046533 W US2024046533 W US 2024046533W WO 2025059405 A1 WO2025059405 A1 WO 2025059405A1
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spg11
neurons
group
cholesterol
alkyl
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Xuejun Li
Eric Chai
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University of Illinois at Urbana Champaign
University of Illinois System
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University of Illinois at Urbana Champaign
University of Illinois System
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    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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

Definitions

  • HSPs hereditary spastic paraplegias
  • HSPs are further divided into autosomal dominant, autosomal recessive and X-linked inheritance (Finsterer et al. (2012) J. Neurol. Sci. 318:1-18).
  • Spastic paraplegia type 11 (SPG11) is one of the most frequent autosomal recessive forms of HSP caused by mutations in the SPG11 gene that encodes spatacsin protein (Denora et al. (2013) Handb. Clin. Neurol. 113:1899-1912; Fink (2013) Acta Neuropathol. 126:307-328; Stevanin et al. (2008) Brain 131:772-784).
  • SPG11 In addition to typical symptoms of HSP such as lower limb spasticity and weakness, SPG11 patients often exhibit cognitive impairment, mental retardation, early-onset parkinsonism, and thin corpus callosum.
  • the SPG11 protein is a binding partner of the SPG15 protein, another common recessive form of HSP. Though both SPG11 and SPG15 proteins have been shown to regulate autophagy lysosome reformation (Rapase et al. (2014) Ann, Clin. Transl. Neurol. 1:379- 389), how impaired lysosomal function leads to axonal degeneration remains elusive.
  • Cholesterol is highly enriched in the central nerve system, critical for maintaining axonal and synaptic functions. It has been shown that the spatacsin protein can regulate cholesterol trafficking and prevent abnormal cholesterol accumulation in lysosomes (Branchu et al. (2017) Neurobiol. Dis. 102:21-37). Spatacsin protein activates clathrin downstream and recruits dynamin to exocytose gangliosides and lipid from lysosomes (Boutry et al. (2019) Commun, Biol. 2:380).
  • LXR Liver X Receptor
  • LXR Liver X Receptor
  • FIG. 1 Quantification of the amount of filipin staining colocalized with LAMP1 in SPG11 knockdown groups treated with GW3965, RGX104, or DMSO (vehicle control).
  • the proportion of cholesterol in lysosome was significantly increased in SPG11 neurons, which was mitigated by the treatment with either LXR agonist.
  • FIG. 2 Neurite outgrowth quantification revealed a significant elongation of Tau + axons in SPG11 knockdown neurons after the treatment of GW3965, RGX104, or DMSO
  • FIG. 3 Quantification of axonal swelling density in long-term cultures revealed a significant reduction of increased axonal swellings in SPG11 knockdown groups (SPG11- A and SPG11-B) by the treatment of GW3965 and RGX104. Both drugs did not show significant effects on axonal swellings density in control Luc neurons. Data were presented as Mean ⁇ SD, *p ⁇ 0.05, **p ⁇ 0.01 versus SPG11 DMSO group by Dunnett's test after ANOVA.
  • FIG. 4 Relative Caspase 3/7 activity was significantly increased in two independent SPG11 knockdown groups (SPG11-A and SPG11-B) compared to Luc control neurons. Data were presented as Mean + SD, ***p ⁇ 0.01 versus luciferase group by Dunnett's test.
  • FIG. 5 Relative Caspase 3/7 activity in both SPG11 knockdown treated with different drugs for 1 week. After treatment with GW3965 or RGX104, the caspase activity was significantly decreased. Data were presented as Mean ⁇ SD, *p ⁇ 0.05, **p ⁇ 0.01, versus DMSO group by two-sided t-test.
  • FIG. 6 Quantification of the relative intensity of filipin staining in plasma membrane (PM) of cortical neurons after treatment of GW3965, RGX104, and DMSO (vehicle). Data were presented as Mean ⁇ SD. **p ⁇ 0.01 versus SPG11 DMSO group by Dunnett's test after ANOVA.
  • FIG. 7 Quantification of axonal swelling density in long-term cultures revealed a significant reduction of increased axonal swellings in SPGll-mutated neurons after the treatment of GW3965 and RGX104. Both drugs did not show significant effects on axonal swellings density in control Luc neurons. Data were presented as Mean ⁇ SD. **p ⁇ 0.01 versus SPG11 DMSO group by Dunnett's test after ANOVA. [0016] FIG. 8, After treatment with LXR agonists and vehicle, the apoptosis levels in SPG11 p.Gln40X neurons were examined by analyzing Caspase 3/7 activities. Data were presented as Mean ⁇ SD. **p ⁇ 0.01 versus SPG11 DMSO group by Dunnett's test after ANOVA.
  • FIG. 9 Effects of non-lipogenic ABCA1 inducers on the apoptosis levels in SPG11 neurons.
  • Cortical neurons were differentiated from SPG11 and normal control human pluripotent stem cells.
  • ABCA1 inducers HSP neurons were treated with different doses of ABCAl-inducing compound, CL3-3, at 0.1 pM, 1 pM, and 3 pM) for one week.
  • the levels of Caspase 3/7 activities in these neurons were then examined using the Caspase 3/7 Gio® assay.
  • Data were presented as Mean ⁇ SD, ⁇ 0.01 versus Control DMSO group, and ##P ⁇ 0.01 versus SPG11 DMSO group by
  • Spastic paraplegia type 11 is a common autosomal recessive form of hereditary spastic paraplegia characterized by the degeneration of cortical motor neuron axons, leading to muscle spasticity and weakness.
  • SPG11 Spastic paraplegia type 11
  • PNs cortical projection neurons
  • a motor neuron disease or condition associated with, caused by, or otherwise attributed to a SPG11 pathogenic variant by administering to a subject in need thereof a LXR agonist thereby treating or ameliorating the subject's disease or condition associated with the SPG11 pathogenic variant.
  • Treating covers the treatment of a motor neuron disease or condition described herein, in a subject, preferably a human, and includes inhibiting a motor neuron disease or condition, i.e., arresting its development; relieving a motor neuron disease or condition, i.e., causing regression of the motor neuron disease or condition; slowing progression of the motor neuron disease or condition; and/or inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.
  • treatment results in a measurable (i.e., at a statistically significant level) decrease or reduction in one or more signs or symptoms of a motor neuron disease or condition.
  • Subject or “subject in need thereof” refers to a warm-blooded animal such as a mammal, preferably a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or motor neuron diseases or conditions described herein.
  • Subjects benefiting from any one of the above referenced treatments include, but are not limited to, subjects at risk of having, having or predisposed to have a motor neuron disease or condition associated with the SPG11 pathogenic variant.
  • SPG11 pathogenic variant refers to a complete or partial deletion or mutation in the SPG11 locus resulting in SPG11 deficiency, e.g., the absence of expression or absence of a functional gene product (e.g., SPG11 mRNA or SPG11 protein).
  • SPG11 pathogenic variants include, but are not limited to, c.H 8C>T (p.Gln4O-STOP), C.3291+1G>T, c.4307_4308delAA (p.Glnl436Argfs), c.200 203delCTTT (p.Ser67fs), c.2987_2989delGTT (p.Cys996del), c.2163dupT (p.Ile722Tyrfs), c .5410___5411delTG (p .Cysl804Profs), c.l203del (p.Asp402fs), C.2316+ 1G-A, c.3121C>T (p.Argl041Ter), p.AlalO6Leufs*15, p.Thrl92AsnfsTerll, p .Met245Valfs*2, p.
  • a motor neuron disease or condition "attributed to a SPG11 pathogenic variant, " “caused by a SPG11 pathogenic variant,” or “associated with a SPG11 pathogenic variant” refers to a motor neuron disease, disorder, or condition in which a SPG11 pathogenic variant (e.g., SPG11 deficiency) has been observed to occur or in which a SPG11 pathogenic variant is known or thought to be associated with or contribute to motor neuron disease etiology, progression, or symptoms, or in which a SPG11 pathogenic variant is known or thought to occur as the motor neuron disease progresses.
  • SPG11 pathogenic variants are associated with a spectrum of clinical manifestations resulting from first and/or second motor neuron degeneration.
  • Motor neuron diseases associated with a SPG11 pathogenic variant include, but are not limited to, a pure or complex hereditary spastic paraplegia (Stevanin et al. (2008) Brain 131:772-84), amyotrophic lateral sclerosis (Orlacchio et al. (2010) Brain 133:591-8; Daoud et al. (2012) Neurobiol. Aging 33:839.e5-9; Manole et al. (2016) J. Neurol. 263:2278-86) and Charcot-Marie-Tooth neuropathy
  • the motor neuron disease or condition is a hereditary spastic paraplegia.
  • Hereditary spastic paraplegia is characterized by progressive spasticity and weakness of the lower limbs freguently associated with mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline, peripheral neuropathy, pseudobulbar involvement, and increased reflexes in the upper limbs.
  • the diagnosis of hereditary spastic paraplegia is established in a proband with characteristic clinical and MRI findings and biallelic pathogenic variants in SPG11 identified on molecular genetic testing.
  • the motor neuron disease or condition is amyotrophic lateral sclerosis.
  • Amyotrophic lateral sclerosis formerly known as Lou Gehrig's disease, is a neurological disorder that affects motor neurons, the nerve cells in the brain and spinal cord that control voluntary muscle movement and breathing. As motor neurons degenerate and die, they stop sending messages to the muscles, which causes the muscles to weaken, start to twitch (fasciculations), and waste away (atrophy). Early symptoms include muscle twitches, muscle cramps, tight and stiff muscles (spasticity), muscle weakness, slurred and nasal speech, and difficulty chewing and swallowing. As the disease progresses, muscle weakness and atrophy spread throughout the body.
  • the motor neuron disease or condition is the Charcot-Marie-Tooth neuropathy.
  • Charcot- Marie-Tooth disease results in smaller, weaker muscles and may cause a loss of sensation and muscle contractions, and difficulty walking. Foot deformities such as hammertoes and high arches also are common. Symptoms usually begin in the feet and legs, but they may eventually affect the hands and arms.
  • the motor neuron disease or condition is multiple sclerosis (MS).
  • MS damages the protective cover around nerves called myelin in your central nervous system. It can cause muscle weakness, vision changes, numbness and memory issues. In addition, common symptoms include fatigue, dizziness, loss of balance, mood changes, and muscle stiffness.
  • a “liver X receptor agonist” or “LXR agonist” refers to an agent capable of activating, enhancing, increasing, or otherwise stimulating one or more functions of the target LXR.
  • the LXR agonist increases the activity of the target LXR by at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, as compared to the target LXR in the absence of the agonist.
  • the LXR is LXRa.
  • the target is LXRp.
  • the LXR agonist selectively agonizes LXRa.
  • the LXR agonist is a nonselective LXR agonist that agonizes LXRa and LXRp. In some embodiments, the LXR agonist selectively agonizes LXR[ ⁇ . In some embodiments, the agonist exhibits at least 2.5-fold selectively for LXRp over LXRa.
  • LXR agonists include, but are not limited to, T0901317 (CAS No. 293754-55-9), GW3965 (3- [3-[[[2-Chloro-3-(trifluoromethyl)phenyl]methyl](2,2- diphenylethyl)amino]propoxy]benzeneacetic acid; CAS No. 405911-17-30, RGX-104 (2-[3-[(3R)-3-[[2-chloro-3-
  • the LXR agonist is RGX-104.
  • the LXR agonist is a compound that increases or induces ABCA1 expression. Examples of such compounds are described in, e.g., US 2024/0199572 Al, incorporated herein by reference in its entirety.
  • the LXR agonist is a compound of Formula (I), or a pharmaceutically acceptable salt or prodrug thereof:
  • X1, X2, X3, X4, X5, X6 X7, X8, X9, X10, and Xu are each independently selected from the group of carbon (C), nitrogen (N), sulfur (S), oxygen (O), NH, or CYi; each occurrence of Yi is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, cyano, halo, alkoxy, ketone, ester, carboxamide, sulfide, sulfoxide, sulfone, sulfonamide, a 5- or 6-membered monocyclic heteroaryl, and a 5- or 6-membered fused-ring;
  • Z5 is S
  • Zi is N or C
  • each occurrence of Y2 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, cyano, and halo, with the proviso that either Zi is not hydrogen, or Zg is alkyl when Z7 is N.
  • the compound is not F420, wherein Zi is hydrogen, and Zg is hydrogen when Z7 is N, [0031]
  • the LXR agonist is a compound of Formula (II), or a pharmaceutically acceptable salt or prodrug thereof:
  • X1 and X2 are each independently selected from the group of C, N, S, O, NH, or CYi; each occurrence of Yi is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, cyano, and halo;
  • Z? is N or C; and each occurrence of Y2 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, cyano, and halo; mi and m2 are independently 0, 1, 2, 3, or 4; m and n2 are independently 0, 1, 2, 3, or 4; and
  • Ri, R2, R3, and R4 are each independently selected from the group of hydrogen, halo, hydroxy, nitro, C1-C6 alkyl, alkoxy, ketone, ester, carboxamide, sulfide, sulfoxide, sulfone, sulfonamide, C1-C6 fluoroalkyl, cyano, -O(C1-C6 alkyl), and -0 (C1-C6fluoroalkyl), with the proviso that either Zi is not hydrogen, or Z@ is alkyl when Z 7 is N.
  • X is S, 0, or NH
  • Zi, Z2, Z3, Z5, and Ze are each independently selected from the group of hydrogen, halo, 0, S, N, NH, CH2, hydroxy, or
  • Z4 is S; each occurrence of Yi is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, cyano, and halo; mi and m2 are independently 0, 1, 2, 3, or 4; m and n2 are independently 0, 1, 2, 3, or 4; and
  • Ri, R2, R3, and Ro are each independently selected from the group of hydrogen, halo, hydroxy, nitro, C1-C6 alkyl, alkoxy, ketone, ester, carboxamide, sulfide, sulfoxide, sulfone, sulfonamide, C1-C6 fluoroalkyl, cyano, -O(C1-C6 alkyl), and -0 (C1-C6fluoroalkyl, with the proviso that either Zi is not hydrogen, or Ze is alkyl.
  • the LXR agonist is a compound of Formula (IV), or a pharmaceutically acceptable salt or prodrug thereof:
  • X is S, 0, or NH
  • Z4 is S; each occurrence of Yi is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, cyano, and halo; mi and m2 are independently 0, 1, 2, 3, or 4; ni is independently 0, 1, 2, 3, or 4;
  • 01 and 02 are independently 0, 1, 2, 3, or 4;
  • Ri, R2, R3, R4and R5 are each independently selected from the group of hydrogen, halo, hydroxy, nitro, C1-C6 alkyl, alkoxy, ketone, ester, carboxamide, sulfide, sulfoxide, sulfone, sulfonamide, C1-C6 fluoroalkyl, cyano, “O(C1-C6 alkyl), and -0 (C1-C6 fluoroalkyl), with the proviso that either Z1 is not hydrogen, or Z6 is alkyl.
  • the LXR agonist is a compound of Formula (V), or a pharmaceutically acceptable salt or prodrug thereof:
  • Z1 and Z2 are each independently selected from the group of N, S, 0, NH, CH, or NYi, each occurrence of Yi is independently selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl; mi and m2 are independently 0, 1, 2, 3, or 4; nx and n2 are independently 0, 1, 2, 3, or 4; and
  • Ri, R2, R3 and R4 are each independently selected from the group of hydrogen, halo, hydroxy, nitro, C1-C6alkyl, alkoxy, ketone, ester, carboxamide, sulfide, sulfoxide, sulfone, sulfonamide, C1-C6 fluoroalkyl, cyano, -OfC1-C6 alkyl), and - O(C1-C6 fluoroalkyl).
  • the LXR agonist is a compound of Formula (VI), or a pharmaceutically acceptable salt or prodrug thereof:
  • Zi, Z2, Z3, and Z4 are each independently selected from the group of N, S, 0, NH, CH, or NYi; each occurrence of Yi is independently selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl; mi and m2 are independently 0, 1, 2, 3, or 4; ni and n2 are independently 0, 1, 2, 3, or 4; and
  • Ri, R2, R3 and R4 are each independently selected from the group of hydrogen, halo, hydroxy, nitro, C1-C6alkyl, alkoxy, ketone, ester, carboxamide, sulfide, sulfoxide, sulfone, sulfonamide, C1-C6 fluoroalkyl, cyano, -O(C1-C6 alkyl), or - O(C1-C6fluoroalkyl) .
  • the LXR agonist is a compound of Formula (VII), or a pharmaceutically acceptable salt or prodrug thereof:
  • Ri, R2, R3 and R4 are each independently selected from the group of hydrogen, halo, hydroxy, nitro, C1-C6alkyl, alkoxy, ketone, ester, carboxamide, sulfide, sulfoxide, sulfone, sulfonamide, C1-C6 fluoroalkyl, cyano, -O(C1-C6 alkyl), or - O(C1-C6fluoroalkyl) .
  • the LXR agonist is a compound of Formula (VIII), or a pharmaceutically acceptable salt or prodrug thereof:
  • Ring B is selected from
  • the LXR agonist is a compound of Formula (IX), or a pharmaceutically acceptable salt or prodrug thereof:
  • Ring B is selected from
  • Ri is hydrogen, halo, alkyl, alkoxy, COaMe, CChEt, cyano, or OCF3;
  • R2 and R3 are each independently selected from the group of alkoxy, alkyl, halo, or cyano.
  • the LXR agonist is a compound of Formula (X), or a pharmaceutically acceptable salt or prodrug thereof :
  • Ring B is selected from
  • R1 and R2 are each independently selected from the group of hydrogen, halo, alkyl, alkoxy, C02Me, COsEt, cyano, or OCF 3 ;
  • R3 and R4 are each independently selected from the group of alkoxy, alkyl, halo, or cyano.
  • the LXR agonist is a compound of
  • Ri and R2 are each independently selected from the group of hydrogen, halo, alkyl, alkoxy, COzMe, COzEt, cyano, or OCF3;
  • R3 and Rs are each independently selected from the group of alkoxy, alkyl, halo, or cyano.
  • halo refers to a fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I) group. In certain aspects, “halo” or “halogen” refers to a Cl or F group.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms unless otherwise specified.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tertbutyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n- heptyl, n-octyl, n-nonyl, and n-decyl.
  • the groups disclosed herein are delineated by a specified number of carbon atoms, e.g., Ci- C6-
  • the numerical range "1 to 6" or “1-6” refers to each integer in the given range, e.g., "1 to 6 carbon atoms” means that a group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from among methyl, ethyl, propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, and t-butyl.
  • C1-C4 alkyl includes C1-C2 alkyl and C1-C3 alkyl.
  • Alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • haloalkyl as used herein, means at least one halogen, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • each "haloalkyl” is a fluoroalkyl, for example, a polyfluoroalkyl such as a substantially perfluorinated alkyl.
  • hydroxyalkyl means an alkyl group, as defined herein, with one or more (e.g., 1, 2 or 3) hydroxy substituents.
  • sulfide refers to a group having the structure -S-Rf, where Rf may be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl.
  • Rf may be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl.
  • sulfide groups include a methylthio group, an ethylthio group, a t-butylthio group, and a tert-butylthio group.
  • Rings refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings can be monocyclic or fused-ring, i.e., polycyclic. Rings can be optionally substituted.
  • carbocycles e.g., aryls and cycloalkyls
  • heterocycles e.g., heteroaryls and non-aromatic heterocycles
  • aromatics e.g., aryls and heteroaryls
  • non-aromatics e.g., cycloalkyls and non-aromatic heterocycles.
  • Rings can be monocyclic or fuse
  • membered ring can embrace any cyclic structure.
  • membered is meant to denote the number of skeletal atoms that constitute the ring.
  • cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5- membered rings.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system, which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituent may also mean a single moiety that simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moieties are methylenedioxy, ethylenedioxy, -C(CH3)2“ and the like.
  • aryl means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system.
  • the bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl.
  • the bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring.
  • the fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and/or thia groups.
  • bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-l-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl,
  • the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, or a 5- or 6-membered monocyclic heterocyclyl , wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted.
  • the aryl group is phenyl or naphthyl. In certain other embodiments, the aryl group is phenyl.
  • cycloalkyl as used herein, means a monocyclic or a bicyclic cycloalkyl ring system.
  • Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain aspects, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings.
  • Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two nonadjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH2) W “, where w is 1, 2, or 3).
  • bicyclic ring systems include, but are not limited to, bicyclo [3.1.1]heptane, bicyclo [2.2.1]heptane, bicyclo [2.2.2]octane, bicyclo [3.2.2]nonane, bicyclo [3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6- membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.
  • heteroaryl means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring.
  • the monocyclic heteroaryl can be a 5- or 6-membered ring.
  • the 5-membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom.
  • the 6-membered ring consists of three double bonds and one, two, three or four nitrogen atoms.
  • the 5- or 6-membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl.
  • monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted.
  • the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system.
  • the bicyclic heteroaryl is a monocyclic heteroaryl fused to a phenyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system.
  • bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6- dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-l-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl , quinolinyl, purinyl, 5,6,7,8- tetrahydroquinolin-2-yl, 5, 6,7,8-tetrahydroquinolin-3-yl,
  • the fused bicyclic heteroaryl is a 5- or 6-membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted.
  • heterocyclyl as used herein, means a monocyclic heterocycle or a bicyclic heterocycle.
  • the monocyclic heterocycle is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of 0, N, and S where the ring is saturated or unsaturated, but not aromatic.
  • the 5-membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the 6-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of 0, N' and S.
  • the monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle.
  • monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl , isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl , oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thi
  • the bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl.
  • the bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.
  • bicyclic heterocyclyls include, but are not limited to, 2,3- dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin- 1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2- yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro- iH-indolyl, and octahydrobenzofuranyl.
  • Heterocyclyl groups are optionally substituted.
  • the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring fused to phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted.
  • saturated means the referenced chemical structure does not contain any multiple carbon-carbon bonds.
  • a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like.
  • '''unsaturated means the referenced chemical structure contains at least one multiple carbon-carbon bond but is not aromatic.
  • an unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.
  • the compounds herein include the compounds themselves as well as tautomers, salts, solvates, amides, and/or esters thereof.
  • Exemplary compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), Formula (IX), Formula (X), or Formula (XI), include, but are not limited to:
  • “Pharmaceutically acceptable salts” refers to salts or zwitterionic forms of the present compounds. Salts of the present compounds can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation.
  • the pharmaceutically acceptable salts of the present compounds can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, tartaric, and citric.
  • Nonlimiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pival
  • available amino groups present in the compounds of the disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • any reference to compounds herein is intended to include the present compounds as well as pharmaceutically acceptable salts thereof.
  • the LXR agonist may be provided in a pharmaceutical composition
  • a pharmaceutical composition comprising the LXR agonist, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, or carriers.
  • the pharmaceutical composition may be used, for example, for treating motor neuron diseases such as amyotrophic lateral sclerosis and hereditary spastic paraplegias .
  • a pharmaceutical composition that includes a LXR agonist together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients.
  • excipients include liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like.
  • the term "pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a LXR agonist of the disclosure is administered.
  • the terms "effective amount” or “pharmaceutically effective amount” refer to a nontoxic but sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.
  • “Pharmaceutically acceptable carriers” for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, latest edition.
  • sterile saline and phosphate-buffered saline at physiological pH can be used.
  • Preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical composition.
  • sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid can be added as preservatives.
  • antioxidants and suspending agents can be used.
  • Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences, latest edition.
  • auxiliary substances such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, can be present in such vehicles.
  • a biological buffer can be any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Trisbuffered saline, Hank's-buffered saline, and the like.
  • the pharmaceutical compositions can be in the form of solid, semisolid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.
  • compositions herein will be administered in a therapeutically effective amount by any of the accepted modes of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication toward which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease.
  • compositions herein may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • oral including buccal and sub-lingual
  • rectal including nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • parenteral including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous administration or in a form suitable for administration by inhalation or insufflation.
  • the preferred manner of administration is intravenous or oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
  • permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).
  • polycations chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin
  • polyanions N-carboxymethyl chitosan, poly-acrylic acid
  • thiolated polymers carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thiog
  • the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well.
  • suitable inert carrier such as ethanol, glycerol, water, and the like
  • flavoring, coloring and/or sweetening agents can be added as well.
  • Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
  • Parenteral formulations may be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system.
  • a formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Preparations according to the disclosure for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.
  • Sterile injectable solutions are prepared by incorporating one or more of the LXR agonists herein in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-f iltered solution thereof.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
  • compositions herein may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable nonirritating excipient include cocoa butter, beeswax and polyethylene glycols .
  • compositions herein may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.
  • Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives.
  • Creams containing the selected active agent are, as known in the art, viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil.
  • Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • the specific ointment or cream base to be used is one that will provide for optimum drug delivery.
  • an ointment base should be inert, stable, nonirritating and nonsensitizing .
  • Formulations for buccal administration include tablets, lozenges, gels and the like. Alternatively, buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art.
  • the compounds of the disclosure can also be delivered through the skin or muscosal tissue using conventional transdermal drug delivery systems, i.e., transdermal "patches" wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface.
  • the drug composition is typically contained in a layer, or "reservoir, " underlying an upper backing layer.
  • the laminated device can contain a single reservoir, or it can contain multiple reservoirs.
  • the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
  • the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, can be either a polymeric matrix as described above, or it can be a liquid or gel reservoir, or can take some other form.
  • the backing layer in these laminates which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility.
  • the material selected for the backing layer should be substantially impermeable to the active agent and any other materials that are present.
  • the LXR agonists herein may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the agonist will generally have a small particle size for example of the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol can conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition can be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder can be administered by means of an inhaler.
  • a pharmaceutically or therapeutically effective amount of the composition will be delivered to the subject.
  • the precise effective amount will vary from subject to subject and will depend upon the species, age, the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration.
  • the effective amount for a given situation can be determined by routine experimentation.
  • generally a therapeutic amount will be in the range of about 0.01 mg/kg to about 250 mg/kg body weight, more preferably about 0.1 mg/kg to about 10 mg/kg, in at least one dose.
  • the indicated daily dosage can be from about 1 mg to 300 mg, one or more times per day, more preferably in the range of about 10 mg to 200 mg.
  • the subject can be administered as many doses as is required to reduce and/or alleviate the signs, symptoms, or causes of the disorder in question, or bring about any other desired alteration of a biological system.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the LXR agonist may be administered alone or in combination with other therapeutics (e.g., antispasmodic medications, medications for treating cognitive symptoms, and/or disease-modifying therapies) in the treatment of the motor neuron disease or disorder.
  • therapeutics include, e.g., riluzole, edaravone, sodium phenylbutyrate/taurursodiol, tofersen, baclofen, tizandine, botulinum, gabapentin, nortriptyline, donepezil, beta interferon, glatiramer acetate, ofatumumab, alemtzuumab, natalizumab, rituximab, ocrelizumab, ublituximab, cladribine, dimethyl fumarate, diroximel fumarate, fingolimod, siponimod, ponesimod, oxanimod, and teriflunomide ,
  • Lentiviruses were packaged using a calcium phosphate transfection method as described previously (Denton et al. (2014) Stem Cells 32:414-423). Briefly, pLKO.l shRNA plasmid, psPAX2 packaging plasmid and pMD2.G envelope plasmid were mixed and then incubated in calcium phosphate solution with 2x HEPES-buffered saline for 1 minute. The mixture was transferred into dishes for co-culturing the cocktail with HEK293T cells.
  • the viral particles from the cell culture medium were collected through 20,000 rpm ultracentrifugation (SW28 rotor, Beckman) at 16°C for 2 hours and the pellet was resuspended in hESC medium.
  • SW28 rotor For stable transfection of H9 ESCs (WA09, WiCell Research Institute), cells were dissociated to small clusters and then incubated with viruses at 37°C for 30 minutes. With the Blasticidin selection, the hESCs with stable transfection survive while other cells including feeder cells gradually die. The Blasticidin-resistant cells were then dissociated to select clonal SPG11 knockdown hESC cell lines. With knockdown efficacy confirmed by qPCR, both SPG11 knockdown and Luciferase knockdown lines (as controls) were generated for differentiation .
  • hESC aggregates were then cultured in Neural Induction Medium (NIM) and attached to culture dishes as previously described (Boisvert et al. (2013) J. Vis. Exp. (74):50321).
  • NIM Neural Induction Medium
  • the neuroepithelial clusters were isolated and cultured in suspension culture.
  • the neurospheres were cultured in suspension for 3-4 weeks and were then plated onto polyornithine-coated coverslips for terminal differentiation.
  • the cortical PNs were fixed to examine early axonal outgrowth and extension. With further culture, the long-term cultured cortical PNs (over 10 weeks) were used to analyze axonal degeneration. Cells from three independent coverslips in each group were measured and compared.
  • coverslips were mounted on glass slides. Triplicate coverslips were used for each treatment or cell type and at least three blindly-selected images per coverslip were acquired and analyzed (Chen et al. (2022) Brain 145(11):4016-4031).
  • the LAMPl-positive lysosomal area (first) and the soma of the cell (second area) were selected and added to ROI manager.
  • Total fluorescent intensity of the first and the second selection area under the blue channel (cholesterol stained) were quantified, which represent the relative cholesterol level in lysosome and soma separately.
  • the ratio between two values is the proportion of cholesterol accumulation in lysosome (Boutry et al. (2019) Commun. Biol. 2:380).
  • Plasma Membrane Labeling and Analysis of PM Cholesterol Levels Plasma was stained with Deep Red CellMaskTM plasma membrane stain (Invitrogen, 1:1000) for 10 minutes at 37°C. Cells were subsequently washed, fixed and stained with Filipin III using cell-based cholesterol detection kit following the manufacture's protocol (Cayman Chemical) . Images were then taken using a Keyence microscope. To analyze membrane cholesterol levels, plasma membrane was selected in ImageJ and then Filipin levels were measured by overlapping with plasma membrane area.
  • Axonal Swellings Analysis To analyze axonal swellings, cortical neuron cultures at approximately 3 months were stained with the axonal marker, Tau. Axonal swellings are defined as a diameter more than 2 times of the contiguous axons (Cheng et al. (2013) J. Pain 14:941-947; Lauria et al. (2003) Neurology 61:631-636). The swelling density was calculated by swelling number over axonal length in the selected area by using Imaged software as described previously (Mou et al. (2020) Acta Neuropathol. Commun. 8:214).
  • RNA was isolated and 1 pg of RNA was taken for reverse transcription using iScriptcDNA Synthesis Kit (BioRad). For quantitative PCR (qPCR), reactions were performed in a 20 pL mixture containing cDNA, primers, and SYBR® Green Master Mix in the QuantStudio 6 Flex Real-Time PCR System per the manufacturer' s instructions (Applied Biosystems). Gene expression levels were compared with the housekeeping gene GAPDH, and calculated using the comparative CT method.
  • Primers used for qPCR include SPG11, 5'-CTCCTAGTGTCCTGCCATCTGA-3' (SEQ ID NO:3), 5'-GGGCTAGAGAAATGTGGGAGATG-3' (SEQ ID NO:4); GAPDH, 5'-ATGACATCAAGAAGGTGGTG-3' (SEQ ID NO:5), 5'- CATACCAGGAAATGAGCTTG-3' (SEQ ID NO:6).
  • Caspase 3/1 Activity Assay Caspase 3/1 Activity Assay. Caspase 3 and 7 activities are highly related to apoptosis levels in cells and were examined using Caspase-Gio® 3/7 Assay kit (Promega) following the manufacturer's instructions. Briefly, neurons were dissociated with Accutase®, a mild enzyme that shows increased survival for neural cells (Wachs et al. (2003) Lab. Invest. 83:949-962), into single cell suspension. Cells were then seeded onto 96-well plates with the density of 5000 cells/well in 50 pL, lysed and incubated with illuminance substrate by adding 50 pL of caspase-3/7 reagents following the manufacture's protocol (Promega). After incubation for 45 minutes at room temperature, luminescence from each well was measured using a Gen5 microplate reader (BioTek).
  • Live Cell Imaging with MitoTracker® Dye To examine mitochondrial transport, neurons (about 10-week) were stained with 50 nM MitoTracker® Red for 4 minutes and then the coverslips were washed with image medium. The coverslips were picked up and placed upside down in 35 mm glass bottom dishes with pre-added 200 pL image medium. Live-cell imaging was performed with an Olympus 1X83 microscope equipped with an incubation chamber. The cells were kept at 37°C with 5% CO2 while imaging. Images were taken every 5 seconds for 5 minutes. The mitochondrial motile percentage was analyzed by ImageJ software with MultiKymograph plugin and Bio-formats Package, as described previously (Mou et al. (2020) J. Vis. Exp. (156):10.3791/60548).
  • RNAi knockdown hESC lines were established by combining lentiviruses and RNA interference (RNAi).
  • pLKO.l vectors were adopted to express small hairpin RNA (shRNA) sequences that target SPG11 (SPG11 shRNA) and luciferase (Luc shRNA, as controls).
  • SPG11 shRNA small hairpin RNA
  • Luc shRNA luciferase
  • SPG11-A SPG11 RNAi-A
  • SPG11 RNAi-B SPG11 RNAi-B
  • the lentiviruses containing SPG11 and Luciferase shRNA were produced and collected from HEK293T cells, and subsequently used to infect hESCs to generate RNAi hESC lines. After drug selection and passages, clonal hESC lines with uniform GFP expression indicative of shRNA expression were generated. The hESCs were expanded by those GFP positive clusters and differentiated into neurons. It was confirmed that hESCs were differentiated into cortical projection neurons by checking the expression of Ctip2, a marker for subcerebral cortical PNs (Arlotta et al. (2005) Nennon 45:207-221; Li et al.
  • hESCs were differentiated into cortical projection neurons using established methods (Boisvert et al. (2013) J. Vis. Exp. (74):50321; Li et al. (2009) Development 136:4055-4063). Axons are generally derived by the longest neurite, which is involved in the formation of the complex neuronal architecture during development (Tosney & Landmesser (1985) Dev. Biol. 109:193-214). Axonal development was examined and axonal length of Ctip2 + cortical PNs was measured.
  • axonal swellings a marker for degenerated axons
  • Accumulation of axonal swellings is a characteristic pathological change observed in HSP, which is formed by the accumulation of transported cargos caused by impaired transport (Carpenter (1968) Neurology 18:841-851).
  • Tau immunostaining was performed to visualize axonal swellings. The number of axonal swellings was guantified and divided by axonal length according to established methods (Denton et al. (2014) Stem Cells 32:414-423; Mou et al. (2020) Acta Neuropathol. Commun.
  • Deep Red CellMaskTM was used to label plasma membrane. This analysis showed a significant reduction of cholesterol in the plasma membrane of SPG11 shRNA-A and shRNA-B neurons. These data indicate that the loss of spatacsin leads to an alteration of cholesterol distribution in SPG11 neurons.
  • LXRs liver X receptors
  • LXR agonist can restore normal cholesterol trafficking and distribution
  • LXR agonists have any protective effects against axonal defects of SPG11 knockdown neurons. It was demonstrated herein that the absence of spatacsin impaired the neurite outgrowth.
  • the SPG11 neurons were treated with cholesterol- targeting drugs (GW3965 or RGX104 at 1 pM final concentration) (Collins et al. (2002) J. Med. Chem. 45:1963-1966; Tavazoie et al. (2016) Cell 172:825-840 e818) and vehicle control (DMSO), and were cultured for 2 days.
  • both GW3965 and RGX104 significantly increased the neurite length of SPG11 neurons to a level similar to control neurons (FIG. 2).
  • LXR agonists can ameliorate the neurite outgrowth abnormalities observed in hESC-derived SPG11 neurons.
  • Cortical PNs derived from Luc-, SPGll-shRNA-A, and SPGll-shRNA-B hESCs were stained with MitoTracker® dye followed by washing and live cell imaging.
  • the kymographs of mitochondria were analyzed, which can track the trajectories of each mitochondrion within the selected axons segment.
  • the result showed that there was a significant reduction in the percentage of motile mitochondria in SPG11 neurons; over 30% of the mitochondria were motile in control (luciferase knockdown) neurons, whereas in SPG11 neurons, only around 20% of the mitochondria were motile.
  • these data indicated that loss of spatacsin reduced axonal transport of mitochondria and decreased the proportion of motile mitochondria.
  • SPG11 is a common dominant recessive form of HSP, and can be caused by compound or homozygous mutations of the SPG11 gene (Southgate et al. (2010) Neurogenetics 11:379-389; Stevanin et al. (2008) Brain 131:772-784).
  • the diseasecausing mutation c. 118C>T, p.Gln40X
  • H9 SPG11 Gln40X lines were efficiently differentiated into CTIP2+ cortical PNs.
  • the expression of SPG11 mRNA was significantly reduced upon differentiation at both neural progenitors and neuron stages, confirming that loss of Spatacsin function is implicated in SPG11.
  • SPG11 Gln40X neurons the localization of cholesterol in lysosomes, as indicated by the co-localization of Filipin (stained for total Cholesterol) and LAMP1 (marker for lysosomes), was significantly increased.
  • SPG11 Gln40X neurons were treated with GW3965 (1 pM), RGX104 (1 pM), or DMSO (Vehicle control). At 1-week after treatment, the localization of cholesterol in lysosome was compared between different groups. The data revealed that the percentage of Filipin staining co-localized with LAMP1 was significantly reduced after GW3965 or RGX treatment.
  • the LXR agonist exhibits protective effects by mitigating axonal degeneration via regulating cholesterol trafficking in SPGll-mutated neurons.
  • an additional screening assay was conducted, and it was observed that non-lipogenic ABCA1 inducers can also affect HSP neurons.
  • a non-lipogenic ABCA1 inducers i.e., CL3-3 was tested using SPGll-mutated neurons.
  • Cortical neurons were generated from SPG11 disease-mutated human pluripotent stem cells as described herein. These neurons were then treated with different doses of the compound and Vehicle (i.e., DMSO) for one week. Normal neurons derived from normal human pluripotent stem cells were used as controls.
  • DMSO Vehicle
  • Normal neurons derived from normal human pluripotent stem cells were used as controls.
  • To examine the effects of the compound on neurodegeneration disease-related apoptosis was compared by measuring Caspase 3/7 activities using the Caspase-Gio® 3/7 assay (Promega).

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Abstract

Sont divulguées des méthodes et des compositions pour traiter ou améliorer une maladie ou une affection du motoneurone associée à un variant pathogène de paraplégie spastique de type 11 à l'aide d'un agoniste du récepteur X du foie (LXR), plus particulièrement des méthodes et des compositions pour traiter la paraplégie spastique héréditaire et la sclérose latérale amyotrophique à l'aide d'un agoniste de LXR.
PCT/US2024/046533 2023-09-13 2024-09-13 Compositions destinées à être utilisées dans une méthode de traitement d'une maladie ou d'une affection du motoneurone associée à un variant pathogène spg11 Pending WO2025059405A1 (fr)

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