WO2008036733A2

WO2008036733A2 - Methods for treatment of vesicle transport disorders

Info

Publication number: WO2008036733A2
Application number: PCT/US2007/078882
Authority: WO
Inventors: Christine Klein; Andrew D. Gassman; Leena Bhoite; John Manfredi
Original assignee: Myriad Genetics, Inc.
Priority date: 2006-09-19
Filing date: 2007-09-19
Publication date: 2008-03-27
Also published as: WO2008036733A3

Abstract

The invention relates to methods of treating diseases and disorders responsive to the modification of vesicle transport comprising administering to a subject in need thereof an effective amount of a compound according to Formulae (I-V) as defined herein.

Description

APPLICATION FOR LETTERS PATENT for METHODS FOR TREATMENT OF VESICLE TRANSPORT DISORDERS

METHODS FOR TREATMENT OF VESICLE TRANSPORT DISORDERS

CROSS REFERENCE TO RELATED U.S. APPLICATION [0001] This application claims the benefit of U.S. provisional application Serial No. 60/826,139, filed September 19, 2006, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The invention relates to therapeutic compounds and to the use of such compounds for treating diseases and disorders responsive to the modification of vesicle transport.

BACKGROUND OF THE INVENTION

[0003] Therapeutic compounds (e.g. (R)-2-(2-fluoro-4-biphenyl)propionic acid) have been shown to ameliorate the symptoms of Alzheimer's Disease (AD) in transgenic mice coincident with reduced levels of the amyloidogenic peptide, Aβ₄₂ (J Neurochem. 2002 83 : 1009; J Clin Invest 112:440, 2003). The mechanism by which such compounds accomplish this reduction in Aβ₄₂ is uncertain. On the one hand, evidence is accumulating to indicate that compounds can directly inhibit the activity of γ-secretase, the complex responsible for production of Aβ₄₂ (J Clin Invest 112:440, 2003; JBC 279:43419, 2004). However, inhibition of γ-secretase activity may not account completely for the in vivo efficacy of compounds for various reasons. For example, the effective concentrations of compounds in the brain are more than 10-fold below the concentrations required for the compounds' in vitro efficacy using cell lines and membrane preparations (J Clin Invest 112:440, 2003). It remains possible, therefore, that the efficacy of the compounds in animals is at least partially results from its effect on a target other than γ- secretase. [0004] In AD patients axonal transport of vesicles in neurites of senile plaques is compromised (Am J Pathol. 162: 1623, 2003) and microtubule density in affected brain regions is reduced (Acta Neuropathol (Berl). 91 :226, 1996). Such observations have prompted speculation that AD may be a consequence of cytoskeletal defects (J Neuropathol Exp Neurol. 55 : 1023, 1996). Indeed, it has recently been reported that impaired axonal transport results in increased Aβ levels and increased amyloid deposition in mice (Science 307: 1282, 2005). If impaired axonal transport contributes to the production of amyloidogenic Aβ peptides, then the activity of compounds in ameliorating symptoms of AD in vivo may at least partly result from a primary effect on such axonal blocks. That is, compounds of the present invention may relieve axonal blocks and thereby reduce amyloid deposition.

[0005] Furthermore, many neurodegenerative diseases share common features related to vesicle transport and vesicle trafficking. For example, focal bead-like swelling in dendrites and axons (neuritic beading) is thought to be a neuropathological sign in neurodegenerative diseases such as Alzheimer's Disease (Exp. Neurol. 156: 100-1 10, 1999), Parkinson's disease (PD) (Acta. Neuropathol. (Berl) 98: 157-164, 1999) and amyotrophic lateral sclerosis (J. Neurol. Sci. 63 :241-250, 1984; Acta. Neuropathol. (Berl) 94:294-299, 1997). In addition, impaired axonal transport is common to the clinical profile of a variety of neuropathologies, including amyotrophic lateral sclerosis (ALS), Charcot- Marie-Tooth Disease 2 (CMT2), spinal muscular atrophy (SPA), spinal muscular atrophy (SMA), Parkinson's Disease (PD), and hereditary sensory motor neuropathy (HSMN). In certain cases impaired axonal transport has been shown to be the primary defect responsible for disease symptoms. For example, a subset of CMT2 patients has been shown to carry a loss-of-function mutation in the motor domain of a kinesin protein that participates in axonal transport of synaptic vesicle precursors (Cell. 105 :587, 2001). In other cases the relationship between impaired axonal transport and the disease is less clear, although vesicle trafficking is involved. For example, axonal growth defects contribute to the pathophysiology of spinal muscular atrophy (see J Neurobiol. 58:272, 2004), although the role of vesicle trafficking in the growth defects is unclear. Accordingly, compounds of the present invention may be useful in treating diseases and disorders responsive to the modification of vesicle transport.

BRIEF SUMMARY OF THE INVENTION

[0006] The invention relates to methods of treating diseases and disorders responsive to the modification of vesicle transport. In one aspect, the method comprises administering to a subject in need thereof an effective amount of a compound according to Formulae I- V:

(ii)

R,

or pharmaceutically acceptable salts or solvates thereof, wherein:

Ri is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃ (or can be taken together with R₂ to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring); R₂ is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃, (or can be taken together with R₂ to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);

R₃ is chosen from -COOH, -COOR₆, -CONH₂, -CONHR₆, -CONR₆R₇, - CONHSO₂R₆, tetrazolyl, and a -COOH bioisostere;

R₄ is chosen from -Cl, -F, -Br, -I, -CF₃, -OCF₃, -SCF₃, -OCH₃, -OCH₂CH₃, -CN, -CH=CH₂, -CH₂OH, and -NO₂;

R₅ is chosen from -Cl, -F, -Br, -I, -CF₃, -OCF₃, -SCF₃, -OCH₃, -OCH₂CH₃, -CN, -CH=CH₂, -CH₂OH, and -NO₂;

R₆ is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃;

R₇ is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃;

M is an integer chosen from O, 1 , 2, and 3; and

N is an integer chosen from O, 1 , 2, and 3.

[0007] In specific embodiments, the compound is (R)-2-(2-fluoro-4- biphenyl)propionic acid. In certain embodiments, methods are provided for treating and/or delaying the onset of Alzheimer's Disease, or a sign or symptom thereof, or other neurodegenerative diseases such as cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistca, Parkinson's disease, amyotrophic lateral sclerosis, Charcot-Marie-Tooth Disease 2, spinal muscular atrophy, spinal muscular atrophy, and hereditary sensory motor neuropathy. In additional embodiments, methods are provided for treating and/or delaying the onset of other neurodegenerative diseases, or a sign or symptom thereof, such as Neimann-Pick type C disease; multiple sclerosis; Guillain-Barre syndrome; polyQ diseases such as Huntington disease, spinobulbar muscular atrophy, dentatorubral- pallidoluysian atrophy, Kennedy's disease (also know as spinobulbar muscular atrophy [SBMA]), spinocerebellar ataxia 1 , spinocerebellar ataxia 2, spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, and spinocerebellar ataxia 17; traumatic brain and spinal cord injury; hereditary spastic paraplegia, spinal muscular atrophy; tauopathies such as progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP- 17); dementia with Lewy Bodies (DLB); Down syndrome; primary lateral sclerosis; optic neuropathies such as Leber's hereditary optic neuropathy (LHON) and Cuban epidemic of optic neuropathy (CEON); juvenile-onset neuronal ceroid lipofuscinosis (JNCL); and neuronal ceroid lipofuscinoses (NCLs).

[0008] In further embodiments, classes of disease whose natural biology are similar to neurodegenerative disorders or require normal axonal transport may be treated. For example, methods are provided for treating and/or delaying the onset of diseases, or a sign or symptom thereof, such as inflammatory myopathies, including polymyositis, dermatopolymyositis, and inclusion body myositis (IBM); and infectious agents and viral diseases such as rabies, prion encephalopathies such as Creutzfeldt-Jakob disease, HSV-I infection, adenovirus infection, vaccinia virus infection, rabies virus infection, African swine fever virus infection, varicella-zoster virus infection including diseases such as chickenpox and shingles; and HIV-I infection.

[0009] In another aspect of the invention, compositions and methods are provided for treating diseases and disorders responsive to the modification of vesicle transport, comprising administering to a subject in need thereof an effective amount of a compound according to Formulae I-V in combination with at least one additional therapeutic agent.

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0011] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 depicts the effect of (R)-2-(2-fluoro-4-biphenyl)propionic acid on invertase secretion from yeast cells.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The invention relates to methods of treating diseases and disorders responsive to the modification of vesicle transport. In one aspect, the method comprises administering to a subject identified to be in need thereof, an effective amount of a compound according to Formulae I-V:

(ii)

R,

or pharmaceutically acceptable salts or solvates thereof, wherein:

R₆ is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃; R₇ is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃; M is an integer chosen from O, 1 , 2, and 3; and N is an integer chosen from O, 1 , 2, and 3.

[0014] Examples of compounds for use in the invention include those as shown above (and below), including enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. The compounds described in this invention disclosure can be made by an ordinary artisan skilled in the art of organic chemistry synthesis.

[0015] Exemplary compounds of Formulae I-V include, 2-methyl-2 (2- fluoro-4'-trifluoromethylbiphen-4-yl) propionic acid; 2-methyl-2 (2-fluoro- 4'cyclohexyl biphen-4-yl) propionic acid; l- (2-fluoro-4'-trifluoromethylbiphenyl- 4-yl) cyclopropanecarboxylic acid; l- (4'-cyclohexyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1 - (4'-benzyloxy-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1 - (2-fluoro-4'-isopropyloxybiphenyl-4-yl) cyclopropanecarboxylic acid; 1 - (2-fluoro-3'-trifluoromethoxybiphenyl-4-yl) cyclopropanecarboxylic acid; 1 - (2-fluoro-4'-trifluoromethoxybiphenyl-4-yl) cyclopropanecarboxylic acid; l- (2-fluoro-3'-trifluoromethylbiphenyl-4-yl) cyclopropanecarboxylic acid; 1- (4'-cyclopentyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1- (4'-cycloheptyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1 - (2'-cyclohexyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1- (2-fluoro-4'-hydroxybiphenyl-4-yl) cyclopropanecarboxylic acid; l-[2-fluoro-4'- (tetrahydropyran-4-yloxy) biphenyl-4- yl] -cyclopropane- carboxylic acid; l- (2, 3',4'-trifluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1- (3', 4'-dichloro-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1- (3', 5'-dichloro-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid 1- (3'-chloro-2, 4'-difluorobiphenyl-4-yl) cyclopropanecarboxylic acid; 1- (4-benzo [b] thiophen-3-yl-3 -fluorophenyl) cyclopropanecarboxylic acid; 1 - (2-fluoro-4'-prop-2-inyloxy-biphenyl-4-yl)- cyclopropanecarboxylic acid; 1- (4'-cyclohexyloxy-2-fluoro-biphenyl-4-yl)- cyclopropanecarboxylic acid; 1- [2-fluoro-4'- (tetrahydropyran-4-yl)-biphenyl-4- yl]-cyclopropanecarboxylic acid; l- [2-fluoro-4'- (4-oxo-cyclohexyl)-biphenyl-4- yl]-cyclopropanecarboxylic acid; 2-(2"-fluoro-4-hydroxy-[l , 1' : 4', 1 "] tert-phenyl- 4"-yl) -cyclopropanecarboxylic acid; l- [4'- (4, 4-dimethylcyclohexyl)-2-fluoro [1 , l'-biphenyl]-4-yl]-cyclopropane- carboxylic acid; l-[2-fluoro-4'-[[4- (trifluoromethyl) benzoyl] ammino] [l , l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid; l -[2-fluoro-4'-[[4-(trifluoromethyl) cyclohexyl] oxy] [l ,l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid; l- [2-fluoro-4'- [ (3, 3,5, 5-tetramethylcyclohexyl) oxy] [l ,l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid; l- [4'- [ (4, A- dimethylcyclohexyl) oxy] -2-fluoro [l , l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid; 1- (2, 3', 4"-trifluoro[l , 1 ': 4',l "-tert-phenyl]-4-yl)-cyclopropanecarboxylic acid; l- (2, 2', 4"-trifluoro[l , 1' : 4',l"-tert-phenyl]-4-yl)-cyclopropanecarboxylic acid; l- (2, 3'-difluoro-4"-hydroxy [1 , 1' : 4', l "-tert-phenyl]-4-yl)-cyclopropane- carboxylic acid; l- (2, 2'-difluoro-4"-hydroxy [1 , 1' : 4',l "-tert-phenyl]-4-yl)- cyclopropane- carboxylic acid; 2- (2-fluoro-3', 5'-bis (chloro) biphen-4-yl) propionic acid amide; 2- (2-fluoro-4'-trifluoromethylbiphen-4-yl) propionic acid; 2- (2-fluoro-3'-trifluoromethylbiphen-4-yl) propionic acid; 2- (2-fluoro-3\ 5'-bis (trifluoromethyl) biphen-4-yl) propionic acid; 2- (4'-cyclohexyl-2-fluorobiphen-4- yl) propionic acid; 2-(2-Fluoro-l , l'-biphenyl-4-yl) -2-methylpropanoic acid; 2- Methyl-2- (3-phenoxy-phenyl)-propionic acid; 2-(4-Isobutyl-phenyl)-2-methyl- propionic acid; 2-(6-Chloro-9H-carbazol-2-yl)-2-methyl-propionic acid; 2-[l- (4- Chloro-benzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]-2-methyl-propionic acid; and 5-[ 1 - (2-Fluoro-biphenyl-4-yl)- 1 -methyl-ethyl]-2H-tetrazole. [0016] In specific embodiments, the compound is (R)-2-(2-fluoro-4- biphenyl)propionic acid. As used herein, the term "(R)-2-(2-fluoro-4- biphenyl)propionic acid" refers to the free acid form of (R)-2-(2-fluoro-4- biphenyl)propionic acid and molar equivalents of various salt forms, substantially free of (S)-2-(2-fluoro-4-biphenyl)propionic acid. (R)-2-(2-fluoro-4- biphenyl)propionic acid is the "R" enantiomer of flurbiprofen ((R,S)-2-(2-fluoro- 4-biphenyl)propionic acid). (R)-2-(2-fluoro-4-biphenyl)propionic acid can be obtained from resolving racemic flurbiprofen or through enantioselective or enantiospecific syntheses. The R-isomer of flurbiprofen ((R)-2-(2-fluoro-4- biphenyl)propionic acid ), or a desired enantiomeric excess of (R)-2-(2-fluoro-4- biphenyl)propionic acid, can then be obtained by resolving the racemic flurbiprofen according to well-known methods, and is also commercially available (e.g., Caymen Chemical, Ann Arbor, MI). Methods of resolving (R)-2-(2-fluoro- 4-biphenyl)propionic acid from the racemate are disclosed in U.S. Pat. No. 5,599,969 to Hardy et al. which discloses reacting racemic flurbiprofen with α- methylbenzylamine to form an isolatable salt of (R)-2-(2-fluoro-4- biphenyl)propionic acid. U.S. Pat. No. 4,209,638 to Boots Co. discloses a process for resolving 2-arylpropionic acids, which include flurbiprofen, by mixing the racemate with a chiral organic nitrogenous base under certain conditions followed by recovery and separation of the diastereomeric salts. Other patents disclosing processes for resolving racemic arylpropionic acids include U.S. Pat. Nos. 4,983,765 to PAZ; 5,015,764 to Ethyl Corp.; 5,235, 100 to Ethyl Corp.; 5,574,183 to Albemarle Corp.; and 5,510,519 to Sumitomo Chemical Company.

[0017] The compound (R)-2-(2-fluoro-4-biphenyl)propionic acid is substantially free of (S)-2-(2-fluoro-4-biphenyl)propionic acid. For example, (R)- 2-(2-fluoro-4-biphenyl)propionic acid may be at least about 90%, at least about 95%, at least about 99%, or at least about 99.9% by weight of the total 2-(2-fluoro- 4-biphenyl)propionic acid (S + R) administered to a patient according to the invention.

[0018] Compounds of the present invention are useful for treatment and/or prevention of any condition, disorder or disease associated with vesicle transport. As used herein, the phrase "vesicle transport disease" means a disease, disorder, or condition responsive to the modification of vesicle transport, that is, a disease, disorder or condition amenable to treatment by modulating vesicle transport. Vesicle transport diseases include diseases such as certain neuropathologies that are characterized by deranged vesicle transport. Vesicle transport diseases also include diseases such as inflammatory myopathies or viral infections in which vesicle transport may be normal or functioning vesicle transport is required but whose onset, symptoms, or progression can nonetheless be alleviated by altering the movement of vesicles.

[0019] Accordingly, the phrase "vesicle transport diseases" includes, but is not limited to, Neiman-Pick type C disease; multiple sclerosis; Guillain-Barre syndrome; polyQ diseases such as Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, Kennedy's disease, spinocerebellar ataxia 1 , spinocerebellar ataxia 1 , spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, and spinocerebellar ataxia 17; traumatic brain and spinal cord injury; hereditary spastic paraplegia; tauopathies such as progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, frontotemporal dementia, and parkinsonism linked to chromosome 17; dementia with Lewy Bodies; Down syndrome; primary lateral sclerosis; optic neuropathies such as Leber's hereditary optic neuropathy, Cuban epidemic of optic neuropathy; prion encephalopathies such as Creutzfeldt-Jakob disease; inflammatory myopathies such as inclusion body myositis, polymyositis, and dermatopolymyositis; juvenile-onset neuronal ceroid lipofuscinosis (JNCL); neuronal ceroid lipofuscinoses (NCLs); and viral diseases such as HSV-I infection, adenovirus infection, vaccinia infection, rabies infection, African swine fever virus infection, varicella-zoster virus infection including diseases such as chickenpox and shingles; and HIV-I infection.

[0020] In one aspect, the invention provides methods for treating or preventing vesicle transport diseases, or a sign or symptom thereof. In specific embodiments, compounds of the present invention are useful for the prevention and/or treatment of Alzheimer's disease, or a sign or symptom thereof, or other neurodegenerative diseases such as cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistca, Parkinson's disease, amyotrophic lateral sclerosis, Charcot-Marie-Tooth Disease 2, spinal muscular atrophy, spinal muscular atrophy, and hereditary sensory motor neuropathy, or a sign or symptom thereof.

[0021] Neimann-Pick type C disease (NPC) is another disease that may benefit from treatment with compounds of the invention. The primary lesion of NPC appears to be impaired cholesterol trafficking and excessive glycosphingolipid storage. One consequence of this impairment is abnormal vesicle trafficking in neural tissue, which likely contributes to the neurodegeneration characteristic of the disease (Neurobiol Aging 26:373, 2005). A recent study indicates that the abnormal vesicle trafficking contributes to increased deposition of Aβ₄₂ in brain tissue of NPC patients (Am J Pathol. 164:975, 2004), which suggests that Aβ peptides may participate in the neurodegeneration. Accordingly, compounds of the invention may be used to treat NPC and/or relieve symptoms of NPC.

[0022] Multiple sclerosis or a sign or symptom thereof may also be treated with compounds of the invention. Inflammation is the cause of much neural damage in multiple sclerosis, resulting in disruption of axonal transport (Curr Opin Neurol. 16:267 ^', 2003). These observations indicate that the neurodegeneration experienced by MS patients may be attenuated by agents that enhance axonal transport. In a similar vein, diseases such as Guillain-Barre syndrome, an inflammatory disorder of the peripheral nerves, may be amenable to therapeutic intervention with agents that enhance axonal transport.

[0023] In addition, polyQ diseases or a sign or symptom thereof may be treated with compounds of the invention. PolyQ diseases involve the expansion of CAG repeats encoding glutamine and are known to cause several late-onset progressive neurodegenerative disorders such as Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, Kennedy's disease (also called spinobulbar muscular atrophy [SBMA]), spinocerebellar ataxia 1 , spinocerebellar ataxia 2, spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, and spinocerebellar ataxia 17. These polyQ disorders commonly exhibit defects in axonal transport {Neuron. 40: 1 , 2003; Neuron 40:25, 2003; Neuron 40:41 , 2003). Indeed, evidence suggests that perturbations in transport pathways are an early event in polyQ disease {Arch Neurol. 62:46, 2005).

[0024] Traumatic brain and spinal cord injury, or a sign or symptom thereof, may also be treated with compounds of the invention. Traumatic brain injury (TBI) is marked by rapid and long-term accumulation of proteins, including beta- amyloid precursor protein. TBI is also an epigenetic risk factor for developing neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease (N euromolecular Med. 4:59, 2003). Therefore, compounds of the invention may be used to treat traumatic injury to both the brain and spinal column.

[0025] Hereditary spastic paraplegia and spinal muscular atrophy are motor neuron diseases that exhibit clear cytoskeletal abnormalities, which suggests the involvement of axonal transport in the pathogenesis of the diseases {Trends Neurosci. 25 :532, 2002). Indeed, a single missense mutation in a vesicle trafficking protein, VAPB, is reported to result in late-onset spinal muscular atrophy (LOSMA) {Am J Hum Genet. 75 :822, 2004). Accordingly, hereditary spastic paraplegia and spinal muscular atrophy or a sign or symptom thereof may be treated by compounds of the invention

[0026] Aberrant functions of the microtubule-associated proteins collectively called tau can lead to neurodegenerative disorders like progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) {Biochim Biophys Acta. 1739:240, 2005; Brain Res Brain Res Rev. 33 :95, 2000). One feature of tauopathies is the disruption of axonal transport that accompanies them. Accordingly, compounds of the invention may also be used to treat tauopathies, or a sign or symptom thereof.

[0027] Dementia with Lewy Bodies (DLB) is characterized by the presence of cytoplasmic inclusions of alpha-synuclein in the cerebral cortex and in the nuclei of the brain stem Arch Gerontol Geriatr 39: 1 , 2004). Protein aggregates, whether they are aggregates of tau, Aβ, prions or other proteins, apparently disrupt vesicle transport. A therapy that relieves symptoms of one disease with protein aggregates (e.g. AD) is therefore a candidate therapy for other diseases that show protein aggregates. Given the numerous similarities of DLB and AD, compounds of the invention are believed to be effective in treating DLB or a sign or symptom thereof.

[0028] Nearly all individuals with Down syndrome develop the neuropathologic lesions of AD by the age of 45 (Arch Neurol 46:849, 1989). Thus, compounds of the invention may moderate or delay the onset of certain features of the dementia of Down syndrome.

[0029] Histological evidence suggests impaired axonal transport of mitochondria in optic neuropathies such as Leber's hereditary optic neuropathy (LHON) and in Cuban epidemic of optic neuropathy (CEON). Furthermore, like synaptic vesicles, mitochondria are transported along microtubules. Therefore, compounds of the present invention may be used to treat such optic neuropathies, or a sign or symptom thereof.

[0030] Inflammatory myopathies or a sign or symptom thereof may also be treated with compounds of the invention. For example, inclusion body myositis (IBM) is an uncommon chronic inflammatory disorder of skeletal muscle that is characterized by accumulation of Aβ and tau protein (Curr Opin Rheumatol 16:700, 2004). The similarity of this disease and inflammatory myopathies to AD suggests that inflammatory myopathies such as polymyositis, dermatopolymyositis, and IBM may be treatable with compounds of the invention. While treatment may not remove the underlying cause of myopathy, it may promote biochemical alterations that compensate for the loss of normal functions.

[0031] Juvenile-onset neuronal ceroid lipofuscinosis (JNCL), also termed Batten disease, results from mutations in the CLN3 protein (Cell 82:949, 1995), which resides in the membranes of vacuoles and endosomes following synthesis in the ER and transit through the Golgi apparatus (J N euros ci Res. 79:573, 2005). While the function of CLN3 is unknown, certain mutants fail to undergo normal intracellular trafficking, while others appear to be transported like the wild-type protein (Hum MoI Genet 8: 1585, 1999). Curiously, the symptoms of the disease are manifest in the central nervous system, admitting the possibility that there is a neuron-specific component to the disease. It is therefore significant that CLN3 is localized to synaptic vesicles in neurons (Hum MoI Genet 8: 1585, 1999), indicating a function in neuronal endocytosis or exocytosis. Agents that modulate axonal trafficking may therefore be therapeutic for Batten disease.

[0032] Furthermore, there exist variants of Batten disease that are collectively termed neuronal ceroid lipofuscinoses (NCLs). These disorders, which have been reported in a number of mammals, share symptomatic features with Batten disease, but result from mutations in genes other than CLN3, such as CLNl , CLN2, CLN4, CLN5, and CLN6. The similarities of these neuronal disorders to Batten disease suggest the possibility that modulators of axonal trafficking may be useful treatments for these diseases.

[0033] Additional diseases exist that exhibit a natural biology requiring normal axonal transport (J Neurobiol. 58:295, 2004). Such diseases, or a sign or symptom thereof, may be treated with compounds of the present invention. For example, rabies virus spreads centripetally to the central nervous system and spreads within the central nervous system by fast axonal transport. Thus, the virus exploits normal axonal transport for its dissemination. Likewise, prion encephalopathies involve the use of normal vesicle transport pathways. Prions, proteinaceous infectious agents composed of an aberrantly folded protein designated PrP(Sc), cause neurodegenerative diseases such as Creutzfeldt- Jakob disease, bovine spongiform encephalitis in cows, and scrapie in sheep and goats. Progression of these diseases may be slowed by interventions that affect intracellular membrane trafficking. Effective interventions could influence intracellular trafficking of prions themselves or trafficking of PrP(Sc).

[0034] It has recently been reported that axonal transport may be a relevant route of PrP(Sc) spread in the brain (J N euro ch em 88: 155, 2004; Am J Pathol 166:287, 2005). Significantly, recent data point to synapses as principal regions of PrP(Sc) deposition, perhaps accounting for the loss of synapses in prion-associated neurodegeneration (Am J Pathol 166:287, 2005). [0035] It is also thought that prions may spread within an organism via routes that involve intercellular communication (Proc Natl Acad Sci U S A. 101 :9683, 2004; Traffic 6: 10, 2005; Science 308: 1862, 2005). Specifically, prions may use exosomes, which are endosome-derived membrane vesicles released into the extracellular environment upon fusion of multivesicular endosomes with the cell surface. Thus, exosomes secreted by infected cells could serve as vehicles for delivery of prions to surrounding cells. In this way, prions could exploit a normal route of cell-to-cell communication for their propagation within a host.

[0036] Accordingly, it may be possible to influence the spread of prions within an infected individual by modulating vesicle transport in cells that are already infected. By modulating intracellular membrane transport, it may be possible to slow extracellular dissemination of prions and slow the neuronal degeneration consequent to prion infection. Therefore, interventions that interfere with vesicle transport can therefore be used to attenuate the spread within a host of infectious agents that use axonal transport. Specifically, compounds of the invention may be used acutely to limit the propagation within infected persons of infectious agents like rabies and prions.

[0037] Similarly, compounds of the invention may be used to treat viral diseases in which the virus life cycle involves vesicle transport. For example, microtubules are essential for HSV-I (J Cell Biol 136: 1007, 1997) and adenovirus (J Cell Biol 144:657, 1999) to reach the nucleus of infected cells. Vaccinia virus exploits first the microtubule network for its intracellular movement (EMBO J 12:3932, 2000) and then the actin cytoskeleton to enhance its cell-to-cell spread (Nat Cell Biol 3 :992, 2001). In addition to rabies virus (J Virol 2000, 74: 10212; J Gen Virol 2001 , 82:2691), African swine fever virus uses microtubules for movement in cells (J Virol 2001 , 75 :9819). HIV-I particles migrate along microtubules (J Cell Biol 2002, 159:441), and distinct classes of retroelements may use the dynein-dynactin complex motor on the MT network to make their way to or from the nucleus, through the cytoplasm. "Varicella-zoster virus, the cause of chickenpox and shingles, also requires the vesicular transport machinery of the host cell for replication (J Virol. 68:6372, 1994). Disruption of vesicular transport within an infected cell should therefore attenuate both intercellular spread of the virus and emergence of once-latent virus following its activation."

[0038] Additional diseases that may be treated with the compound of the invention also include:

[0039] Optic neuropathies: Histological evidence suggests impaired axonal transport of mitochondria in Leber's hereditary optic neuropathy (LHON) and in Cuban epidemic of optic neuropathy (CEON). Since mitochondria are transported along microtubules by mechanisms similar to microtubule-directed transport of vesicles, the pyrrole derivatives of the present invention could potentially be used to treat these diseases, or reduce or reverse their symptoms.

[0040] Diabetic neuropathy (DN): In addition to the involvement of impaired axonal transport, or impaired vesicle trafficking, in the pathoetiology of the neurodegenerative diseases and disorders outlined above, diabetic neuropathy is also characterized by impaired axonal transport. (See McLean, Neurochem Res. 22:951-956 (1997) and Schoemaker, Diabetes Care. 17: 1362 (1994).) In certain rodent models of diabetes expression deficits occur in nerve growth factor (NGF), and in its high-affinity receptor, trkA. These expression deficits lead to decreased retrograde axonal transport of NGF, decreased support of NGF-dependent sensory neurons, and reduced expression of neuropeptides, substance P, and calcitonin gene-related peptide (CGRP). (Tomlinson, et al., Philos. Trans. R. Soc. Lond. B. Biol. Sci. 351 :455-462 (1996)) Hence, compounds that enhance vesicle trafficking in neurons, such as the pyrrole derivatives of the instant invention, may also be useful for the treatment or prophylaxis of DN.

[0041] Thus, any individual having, or suspected of having ALS; PD; CMT2; SMA; HSMN; LOSMA; poly Q diseases including Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, Kennedy's disease (SBMA), spinocerebellar ataxia 1 , spinocerebellar ataxia 2, spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, and spinocerebellar ataxia 17; traumatic brain and spinal cord injury; HSP; MS; Guillain-Barre syndrome; PLS; taupathies including supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP- 17); DLB; NPC; optic neuropathies including LHON and CEON; or DN can be treated using the compositions and methods of the present invention,

[0042] In another aspect of the invention, compositions and methods are provided for treating diseases and disorders responsive to the modification of vesicle transport, or symptoms thereof, comprising administering to a subject identified to be in need thereof an effective amount of a compound according to Formulae I-V in combination with at least one additional therapeutic agent. Generally, the additional therapeutic agent will be one that is useful for treating the disorder of interest. Exemplary additional therapeutic agents do not diminish the effects of the primary agent(s) and/or potentiate the effect of the primary agent(s).

[0043] Use of an additional therapeutic agent in combination with a compound of Formulae I-V can result in less of any of the Formulae I-V compounds and/or less of the additional agent being needed to achieve therapeutic efficacy. In some instances, use of less of an agent can be advantageous in that it provides a reduction in undesirable side effects. In specific embodiments, the compound to be administered in combination with an additional therapeutic agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

[0044] The compounds of Formulae I-V and the additional therapeutic agents may be administered separately or together in a single composition. The compounds of Formulae I-V and the additional therapeutic agents may be administered at the same time or may be administered at different times of the day.

[0045] The compounds for use in the methods of the invention and compositions of the invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to animals, e.g., mammals, orally at a dose of 0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a mammal being treated. In one example, approximately 0.01 to approximately 10 mg/kg of body weight is orally administered. For intramuscular injection, the dose is generally approximately one-half of the oral dose. For example, a suitable intramuscular dose would be approximately 0.0025 to approximately 25 mg/kg of body weight, and from approximately 0.01 to approximately 5 mg/kg of body weight. If an overactive bladder or urinary incontinence therapeutic agent is also administered, it is administered in an amount that is effective to achieve its intended purpose. The amounts of such overactive bladder or urinary incontinence therapeutic agents effective for treating such disorders are well known to those skilled in the art.

[0046] Exemplary daily dosages of compounds of Formulae I-V, such as (R)-2-(2-fluoro-4-biphenyl)propionic acid, are from about 1 mg to about 2000 mg, from about 1 mg to about 1600 mg, from about 1 mg to about 800 mg, and from 1 mg to about 600 mg. Additional exemplary daily dosages of compounds of Formulae I-V, such as (R)-2-(2-fluoro-4-biphenyl)propionic acid, are at least 2000 mg/day, at least 1600 mg/day, at least 800 mg/day, at least 600 mg/day, at least 400 mg/day, at least 300 mg/day, at least 250 mg/day, at least about 200 mg/day, at least about 150 mg/day, and at least about 100 mg/day.

[0047] In a specific example, a daily dose of 1600 mg (R)-2-(2-fluoro-4- biphenyl)propionic acid (given as two 400 mg (R)-2-(2-fluoro-4- biphenyl)propionic acid tablets, BID) is administered to a patient. In another example, a daily dose of 800 mg (R)-2-(2-fluoro-4-biphenyl)propionic acid (given as two 400 mg (R)-2-(2-fluoro-4-biphenyl)propionic acid tablets, BID) is administered to a patient.

[0048] In a topical formulation, the compound may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.

[0049] In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations that may be used pharmaceutically. For example, the preparations, particularly those preparations which may be administered orally and that may be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations that may be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, may contain from approximately 0.01 to 99 percent, from approximately 0.25 to 75 percent of active compound(s), together with the excipient.

[0050] Also included within the scope of the present invention are the nontoxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like. Basic salts are formed by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, Λf-methyl-glucamine and the like.

[0051] The pharmaceutical compositions of the invention may be administered to any animal, which may experience the beneficial effects of the compounds of the invention. Foremost among such animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be so limited.

[0052] The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0053] The pharmaceutical preparations of the present invention are manufactured in a manner, which is itself known, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.

[0054] Suitable excipients are, in particular: fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, using, e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxy- propymethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active compound doses.

[0055] Other pharmaceutical preparations, which may be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active compounds in the form of: granules, which may be mixed with fillers, such as lactose; binders, such as starches; and/or lubricants, such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

[0056] Possible pharmaceutical preparations, which may be used rectally include, e.g., suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, e.g., natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules, which consist of a combination of the active compounds with a base. Possible base materials include, e.g., liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0057] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, e.g., water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400), or cremophor, or cyclodextrins. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.

[0058] The topical compositions of this invention may be formulated as oils, creams, lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12). The preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers are found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0059] Creams may be formulated from a mixture of mineral oil, self- emulsifying beeswax and water in which mixture of the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. A typical example of such a cream is one which includes approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil.

[0060] Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes approximately 30 % almond oil and approximately 70 % white soft paraffin by weight.

[0061] The following examples are illustrative, but not limiting, of the methods and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.

EXAMPLE 1 Effect of Compounds on Yeast Secretory Genes

[0062] This Example tests the sensitivity to (R)-2-(2-fluoro-4- biphenyl)propionic acid of yeast strains that are heterozygous for either of two secretory genes, SEClO/seclO and SEC3/sec3. Both SEClO and SEC3 are essential genes and their proteins products are components of a multiprotein complex, the exocyst, which mediates the targeting and tethering of post-Golgi secretory vesicles for subsequent membrane fusion (Int Rev Cytol. 233 :243, 2004). We found that in the presence of 300 mM (R)-2-(2-fluoro-4-biphenyl)propionic acid SEC3/sec3 heterozygotes grew at 64% and SEClO/seclO heterozygotes grew at 25% the rate of wild-type yeast; whereas in the absence of(R)-2-(2-fluoro-4- biphenyl)propionic acid the heterozygotes grow at rates equivalent to wild-type yeast. Therefore, SEClO/seclO and SEC3/sec3 heterozygotes are more sensitive than wild-type yeast to(R)-2-(2-fluoro-4-biphenyl)propionic acid. EXAMPLE 2 Effect of Compounds on Invertase Secretion

[0063] This Example determines the effect of (R)-2-(2-fluoro-4- biphenyl)propionic acid on secretion of the enzyme invertase from wild-type yeast. Agents that interfere with the movement of secretory vesicles are expected to reduce secretion of invertase.

[0064] Yeast strain MY148 (genotype MATa/α his3Δl/his3Δl leu2Δ0/leu2Δ0 metl 5Δ0/METΔ15 lys2Δ0/LYSΔ2 ura3Δ0/ura3Δ0) was grown overnight in synthetic complete medium containing 2% glucose (SD medium) to repress expression of invertase. After sub-culturing, the cells were grown for an additional 2 hours in SD medium supplemented with 0, 50, 100, 200, or 300 mM (R)-2-(2-fluoro-4-biphenyl)propionic acid. Invertase expression was then initiated by washing the cells into synthetic complete medium containing 0.2% fructose and supplemented with the appropriate concentrations of (R)-2-(2-fluoro-4- biphenyl)propionic acid. Eighty minutes later samples were taken for determination of both secreted invertase activity (enzyme activity in the medium) and total invertase activity (enzyme activity in medium and cells). The values of each sample were plotted as shown in Figure 1 as means ± standard deviation (N=3) and calculated as the ratio of secreted invertase to total invertase as normalized to the control sample ratio with no (R)-2-(2-fluoro-4- biphenyl)propionic acid. The results of this example show that (R)-2-(2-fluoro-4- biphenyl)propionic acid significantly reduced the release of invertase into the extracellular medium.

[0065] All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The mere mentioning of the publications and patent applications does not necessarily constitute an admission that they are prior art to the instant application.

[0066] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A method for treating or delaying the onset of a disease or disorder responsive to the modification of vesicle transport, or sign or symptom thereof, comprising administering to an animal in need thereof an effective amount of a compound according to Formulae I-V:

(R₄)n

(HI) R,

or pharmaceutically acceptable salts or solvates thereof, wherein:

Ri is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃ (or can be taken together with R₂ to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);

R₂ is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃, (or can be taken together with R₂ to give a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexyl ring);

R₆ is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃; R₇ is chosen from -CH₃, -CH₂CH₃, -CH₂CH₂CH₃, and -CH₂CH₂CH₂CH₃;

M is an integer chosen from 0, 1 , 2, and 3; and N is an integer chosen from 0, 1 , 2, and 3.

2. The method of claim 1 wherein the compound is chosen from:

2-methyl-2 (2-fluoro-4'-trifluoromethylbiphen-4-yl) propionic acid;

2-methyl-2 (2-fluoro-4'cyclohexyl biphen-4-yl) propionic acid;

1- (2-fluoro-4'-trifluoromethylbiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (4'-cyclohexyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (4'-benzyloxy-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (2-fluoro-4'-isopropyloxybiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (2-fluoro-3'-trifluoromethoxybiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (2-fluoro-4'-trifluoromethoxybiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (2-fluoro-3'-trifluoromethylbiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (4'-cyclopentyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (4'-cycloheptyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid; l- (2'- cyclohexyl-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (2-fluoro-4'-hydroxybiphenyl-4-yl) cyclopropanecarboxylic acid; l-[2-fluoro-4'- (tetrahydropyran-4-yloxy) biphenyl-4-yl] -cyclopropanecarboxylic acid;

1- (2, 3',4'-trifluorobiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (3', 4'-dichloro-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (3', 5'-dichloro-2-fluorobiphenyl-4-yl) cyclopropanecarboxylic acid 1- (3'- chloro-2, 4'-difluorobiphenyl-4-yl) cyclopropanecarboxylic acid;

1- (4-benzo [b] thiophen-3-yl-3 -fluorophenyl) cyclopropanecarboxylic acid;

1 - (2-fluoro-4'-prop-2-inyloxy-biphenyl-4-yl)-cyclopropanecarboxylic acid;

1 - (4'-cyclohexyloxy-2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid;

1- [2-fluoro-4'- (tetrahydropyran-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid;

1- [2-fluoro-4'- (4-oxo-cyclohexyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid; 2-(2"-fluoro-4-hydroxy-[l , 1' : 4', 1 "] tert-phenyl-4"-yl) -cyclopropanecarboxylic acid;

1- [4'- (4, 4-dimethylcyclohexyl)-2-fluoro [1 , l'-biphenyl]-4-yl]-cyclopropane- carboxylic acid; l-[2-fluoro-4'-[[4-(trifluoromethyl) benzoyl] ammino] [l , l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid; l-[2-fluoro-4'-[[4-(trifluoromethyl) cyclohexyl] oxy] [l , l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid;

1- [2-fluoro-4'- [ (3, 3,5, 5-tetramethylcyclohexyl) oxy] [l , l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid;

1- [4'- [ (4, 4-dimethylcyclohexyl) oxy] -2-fluoro [l ,l'-biphenyl]-4-yl]- cyclopropanecarboxylic acid;

1- (2, 3', 4"-trifluoro[l , 1': 4',l "-tert-phenyl]-4-yl)-cyclopropanecarboxylic acid;

1- (2, 2', 4"-trifluoro[l , 1' : 4',l"-tert-phenyl]-4-yl)-cyclopropanecarboxylic acid;

1- (2, 3'-difluoro-4"-hydroxy [1 , 1' : 4',l "-tert-phenyl]-4-yl)-cyclopropane- carboxylic acid;

1- (2, 2'-difluoro-4"-hydroxy [1 , 1' : 4',l "-tert-phenyl]-4-yl)-cyclopropane- carboxylic acid;

2- (2-fluoro-3', 5'-bis (chloro) biphen-4-yl) propionic acid amide; 2- (2-fluoro-4'- trifluoromethylbiphen-4-yl) propionic acid;

2- (2-fluoro-3'-trifluoromethylbiphen-4-yl) propionic acid;

2- (2-fluoro-3', 5'-bis (trifluoromethyl) biphen-4-yl) propionic acid; 2- (4'- cyclohexyl-2-fluorobiphen-4-yl) propionic acid;

2-(2-Fluoro-l , l'-biphenyl-4-yl) -2-methylpropanoic acid;

2-Methyl-2- (3-phenoxy-phenyl)-propionic acid;

2-(4-Isobutyl-phenyl)-2-methyl-propionic acid; 2-(6-Chloro-9H-carbazol-2-yl)- 2-methyl-propionic acid;

2-[l- (4-Chloro-benzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]-2-methyl- propionic acid; and

5-[ 1 - (2-Fluoro-biphenyl-4-yl)- 1 -methyl-ethyl]-2H-tetrazole.

3. The method of claim 1 wherein the compound is (R)-2-(2-fluoro-4- biphenyl)propionic acid.

4. The method of claim 1 wherein the disease or disorder is chosen from neurodegenerative diseases, polyQ diseases, tauopathies, optic neuropathies, inflammatory myopathies, infectious agents and viral diseases, Hereditary spastic paraplegia, spinal muscular atrophy, traumatic brain and spinal cord injury; dementia with Lewy Bodies, Down syndrome, primary lateral sclerosis, juvenile-onset neuronal ceroid lipofuscinosis, and neuronal ceroid lipofuscinoses.

5. The method of claim 1 wherein the disease or disorder is a neurodegenerative disease chosen from cerebral amyloid angiopathy, HCHWA-D, multi-infarct dementia, dementia pugilistca, Parkinson's disease, amyotrophic lateral sclerosis, Charcot-Marie- Tooth Disease 2, spinal muscular atrophy, spinal muscular atrophy, hereditary sensory motor neuropathy, Neimann-Pick type C disease, multiple sclerosis, and Guillain-Barre syndrome.

6. The method of claim 1 wherein the disease or disorder is a polyQ disease chosen from Huntington disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, Kennedy's, spinocerebellar ataxia 1 , spinocerebellar ataxia 2, spinocerebellar ataxia 3, spinocerebellar ataxia 6, spinocerebellar ataxia 7, and spinocerebellar ataxia

17.

7. The method of claim 1 wherein the disease or disorder is a tauopathy chosen from progressive supranuclear palsy, corticobasal degeneration, Pick's disease, argyrophilic grain disease, and frontotemporal dementia and parkinsonism linked to chromosome 17.

8. The method of claim 1 , wherein said disease or disorder is chosen from hereditary sensory motor neuropathy, diabetic neuropathy, Leber's hereditary optic neuropathy, and Cuban epidemic of optic neuropathy.

9. The method of claim 1 wherein the disease or disorder is an optic neuropathy chosen from Leber's hereditary optic neuropathy and Cuban epidemic of optic neuropathy.

10. The method of claim 1 wherein the disease or disorder is an inflammatory myopathy chosen from polymyositis, dermatopolymyositis, and inclusion body myositis.

11. The method of claim 1 wherein the disease or disorder is an infectious agent or viral disease chosen from Creutzfeldt- Jakob disease, HSV-I infection, adenovirus infection, vaccinia virus infection, rabies virus infection, African swine fever virus infection, varicella-zoster virus infection, chickenpox, shingles, and HIV-I infection.

12. A composition useful for treating diseases and disorders responsive to the modification of vesicle transport, comprising administering to a subject in need thereof an effective amount of a compound according to Formulae I-V or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent that is useful for treating the disorder of interest.

13. The composition of claim 12, wherein the compound according to Formulae I-V is (R)-2-(2-fluoro-4-biphenyl)propionic acid.