Mitofusin activators and methods of use thereof

Abstract

Compositions including small molecule mitofusin activators are described. The mitofusin activators 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. Methods of treatment, pharmaceutical formulations, and screening methods for identifying compounds that activate mitochondrial fusion are also described.

What is claimed is: 
     
         1 . A method comprising:
 administering a therapeutically effective amount of a composition comprising one or more of a mitofusin activator or a pharmaceutically acceptable salt thereof to a subject having or suspected of having a mitochondria-associated disease, disorder or condition, the mitofusin activator having a formula of   
       
         
           
           
               
               
           
         
       
       wherein:
 X is optionally substituted cycloalkyl or heterocycloalkyl; 
 Z is optionally substituted pyridinyl or pyrimidinyl; 
 R a  and R b  are independently selected from the group consisting of H, F, alkyl, and C 3-7  cycloalkyl, or R a  and R b  taken together form a C 3-7  cycloalkyl or heterocycloalkyl; 
 R c  and R d  are independently selected from the group consisting of H, F, alkyl, and C 3-7  cycloalkyl, or R c  and R d  taken together form a C 3-7  cycloalkyl or heterocycloalkyl; 
 Y is O, CR e R f , or cycloalkyl; 
 R e  and R f  are independently selected from the group consisting of H, F, alkyl, and cycloalkyl, or R e  and R f  taken together form C 3-7  cycloalkyl or heterocycloalkyl; 
 o is 0 or 1; 
 p is 1; and 
 q is 0, 1, 2, 3, or 4, provided that if Y is cycloalkyl, the sum of o+p+q is not less than 3 or greater than 5 and otherwise the sum of o+p+q is 5. 
 
     
     
         2 . The method of  claim 1 , wherein R a , R b , R c , R d , R e , and R f  are each independently H or alkyl. 
     
     
         3 . The method of  claim 2 , wherein Y is cyclopropyl or cyclobutyl. 
     
     
         4 . The method of  claim 3 , wherein o is 0. 
     
     
         5 . The method of  claim 2 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 5 , wherein Y is CH 2 , and R a , R b , R c  and R d  are all H. 
     
     
         7 . The method of  claim 2 , wherein Z is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, or 4-pyrimidinyl. 
     
     
         8 . The method of  claim 7 , wherein Y is CH 2 , and R a , R b , R c  and R d  are all H. 
     
     
         9 . The method of  claim 7 , wherein the mitofusin activator is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         10 . 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-generic disorder, physical damage, and/or chemical injury. 
     
     
         11 . The method of  claim 10 , 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; and   crush injury, spinal cord injury (SCI), traumatic brain injury, stroke, optic nerve injury, and related conditions that involve axonal disconnection.   
     
     
         12 . A composition comprising one or more of a mitofusin activator or a pharmaceutically acceptable salt thereof, the mitofusin activator having a formula of 
       
         
           
           
               
               
           
         
       
       wherein:
 X is optionally substituted cycloalkyl or heterocycloalkyl; 
 Z is optionally substituted pyridinyl or pyrimidinyl; 
 R a  and R b  are independently selected from the group consisting of H, F, alkyl, and C 3-7  cycloalkyl, or R a  and R b  taken together form a C 3-7  cycloalkyl or heterocycloalkyl; 
 R c  and R d  are independently selected from the group consisting of H, F, alkyl, and C 3-7  cycloalkyl, or R c  and R d  taken together form a C 3-7  cycloalkyl or heterocycloalkyl; 
 Y is O, CR e R f , or cycloalkyl; 
 R e  and R f  are independently selected from the group consisting of H, F, alkyl, and cycloalkyl, or R e  and R f  taken together form C 3-7  cycloalkyl or heterocycloalkyl; 
 o is 0 or 1; 
 p is 1; and 
 q is 0, 1, 2, 3, or 4, provided that if Y is cycloalkyl, the sum of o+p+q is not less than 3 or greater than 5 and otherwise the sum of o+p+q is 5. 
 
     
     
         13 . The composition of  claim 12 , wherein R a , R b , R c , R d , R e , and R f  are each independently H or alkyl. 
     
     
         14 . The composition of  claim 13 , wherein Y is cyclopropyl or cyclobutyl. 
     
     
         15 . The composition of  claim 14 , wherein o is O. 
     
     
         16 . The composition of  claim 13 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         17 . The composition of  claim 16 , wherein Y is CH 2 , and R a , R b , R c  and R d  are all H. 
     
     
         18 . The composition of  claim 13 , wherein Z is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, or 4-pyrimidinyl. 
     
     
         19 . The composition of  claim 18 , wherein Y is CH 2 , and R a , R b , R c  and R d  are all H. 
     
     
         20 . The composition of  claim 18 , wherein the mitofusin activator is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         21 . The composition of  claim 12 , further comprising:
 a pharmaceutically acceptable excipient.