Trans-4-hydroxycyclohexyl phenyl amide mitofusin activators and methods of use thereof

Abstract

Compounds and compositions including stereoisomers of 6-phenylhexanamide derivative small molecule mitofusin activators are described. In particular, mitofusin activators comprising derivatives of (trans-4-hydroxycyclohexyl)-6-phenylhexanamide, which are useful for treating diseases or disorders associated with a mitochondria-associated disease, disorder, or condition such as diseases or disorders associated with mitofusin-1 (MFN1) and/or mitofusin-2 (MFN2), or mitochondrial dysfunction, are described. Methods of treatment and pharmaceutical formulations are also described.

What is claimed is: 
     
         1 . A method comprising:
 administering a therapeutically effective amount of a composition comprising one or more metabolites of trans-(4-hydroxycyclohexyl)-6-phenylhexanamide or a pharmaceutically acceptable salt thereof to a subject having or suspected of having a mitochondria-associated disease, disorder or condition, the one or more metabolites being active to promote mitofusin activation.   
     
     
         2 . The method of  claim 1 , wherein the one or more metabolites are selected from the group consisting of 
       
         
           
           
               
               
           
         
         and any combination thereof. 
       
     
     
         3 . The method of  claim 1 , wherein the mitochondria-associated disease, disorder or condition is a peripheral nervous system (PNS) or central nervous system (CNS) genetic or non-genetic disorder, physical damage, and/or chemical injury. 
     
     
         4 . The method of  claim 3 , wherein the PNS or CNS disorder is selected from any one or a combination of a chronic neurodegenerative condition wherein mitochondrial fusion, fitness, or trafficking are impaired; a disease or disorder associated with mitofusin 1 (MFN1) or mitofusin 2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, or dysmotility; a degenerative neuromuscular condition such as Charcot-Marie-Tooth disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease; hereditary motor and sensory neuropathy, autism, autosomal dominant optic atrophy (ADOA), muscular dystrophy, Lou Gehrig's disease, cancer, mitochondrial myopathy, diabetes mellitus and deafness (DAD), Leber's hereditary optic neuropathy (LHON), Leigh syndrome, subacute sclerosing encephalopathy, neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP), myoneurogenic gastrointestinal encephalopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), mtDNA depletion, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), dysautonomic mitochondrial myopathy, mitochondrial channelopathy, or pyruvate dehydrogenase complex deficiency (PDCD/PDH); diabetic neuropathy; chemotherapy-induced peripheral neuropathy; crush injury, spinal cord injury (SCI), traumatic brain injury, stroke, optic nerve injury, and related conditions that involve axonal disconnection; and any combination thereof. 
     
     
         5 . A method comprising:
 administering a therapeutically effective amount of a composition comprising trans-(4-hydroxycyclohexyl)-6-phenylhexanamide or a pharmaceutically acceptable salt thereof to a subject having or suspected of having a mitochondria-associated disease, disorder or condition; and   forming one or more metabolites of the trans-(4-hydroxycyclohexyl)-6-phenylhexanamide in vivo within the subject, the one or more metabolites being active to promote mitofusin activation and being selected from the group consisting of   
       
         
           
           
               
               
           
         
         and any combination thereof. 
       
     
     
         6 . The method of  claim 5 , wherein the mitochondria-associated disease, disorder or condition is a peripheral nervous system (PNS) or central nervous system (CNS) genetic or non-genetic disorder, physical damage, and/or chemical injury. 
     
     
         7 . The method of  claim 6 , wherein the PNS or CNS disorder is selected from any one or a combination of a chronic neurodegenerative condition wherein mitochondrial fusion, fitness, or trafficking are impaired; a disease or disorder associated with mitofusin 1 (MFN1) or mitofusin 2 (MFN2) dysfunction; a disease associated with mitochondrial fragmentation, dysfunction, or dysmotility; a degenerative neuromuscular condition such as Charcot-Marie-Tooth disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease; hereditary motor and sensory neuropathy, autism, autosomal dominant optic atrophy (ADOA), muscular dystrophy, Lou Gehrig's disease, cancer, mitochondrial myopathy, diabetes mellitus and deafness (DAD), Leber's hereditary optic neuropathy (LHON), Leigh syndrome, subacute sclerosing encephalopathy, neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP), myoneurogenic gastrointestinal encephalopathy (MNGIE), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS), mtDNA depletion, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), dysautonomic mitochondrial myopathy, mitochondrial channelopathy, or pyruvate dehydrogenase complex deficiency (PDCD/PDH); diabetic neuropathy; chemotherapy-induced peripheral neuropathy; crush injury, spinal cord injury (SCI), traumatic brain injury, stroke, optic nerve injury, and related conditions that involve axonal disconnection; and any combination thereof. 
     
     
         8 . A composition comprising:
 one or more metabolites of trans-(4-hydroxycyclohexyl)-6-phenylhexanamide or a pharmaceutically acceptable salt thereof, the one or more metabolites being active to promote mitofusin activation.   
     
     
         9 . The composition of  claim 8 , wherein the one or more metabolites are selected from the group consisting of 
       
         
           
           
               
               
           
         
         and any combination thereof. 
       
     
     
         10 . The composition of  claim 8 , further comprising:
 a pharmaceutically acceptable excipient.