Anti-arrhythmicity agents

Abstract

Agents, compositions, and methods for regulating cardiac rhythmicity are disclosed.

1 .- 76 . (canceled) 
     
     
         77 . A compound of structure of Formula Ic: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is an alkane, phenyl, heteroaryl, or substituted phenyl group; R 2  is a phenyl, heteroaryl, substituted phenyl, or hydrocarbyl group with or without a heteroatom; and 
         R 3  is an alkoxy, amino, amino ether, N-Boc-protected 2-aminoethoxyethoxyethylamino group, or a C1-C10 straight or branched, acyclic or cyclic alkyloxy group, aryloxy, or amino group with or without heteroatom; and 
         wherein the compound is effective to potentiate mitochondrial Ca 2+  uptake so as to modulate cardiac rhythmicity in a subject. 
       
     
     
         78 . The compound of  claim 77 , wherein R 1  is para-tolyl, R 2  is phenyl, and R 3  is ethoxy. 
     
     
         79 . The compound of  claim 77 , wherein R 1  is orth-fluoro substituted phenyl, a meta-fluoro substituted phenyl, or para-fluoro substituted phenyl. 
     
     
         80 . The compound of  claim 77 , wherein R 3  is ethoxy, menthyloxy, or N-Box-protected 2-aminoethoxyethoxyethalamino group. 
     
     
         81 . The compound of  claim 77 , wherein R 2  is para-fluoro substituted phenyl or a meta-fluoro substituted phenyl. 
     
     
         82 . The compound of  claim 77 , wherein R 3  is ethyl, C3-C6 short alkyl, menthyloxy group, C1-C10 straight or branched, acyclic or cyclic alkyl group, or aryl group. 
     
     
         83 . The compound of  claim 77 , which is in an optically active form. 
     
     
         84 . The compound of  claim 77 , wherein the compound is in an enantiomerically pure form of Formula Ia or Formula Ib: 
       
         
           
           
               
               
           
         
       
     
     
         85 . The compound of  claim 77 , wherein the compound is a compound having the structure of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         86 . A method of regulating cardiac rhythmicity in a subject, comprising potentiating mitochondrial Ca 2+  uptake by
 i) inducing VDAC2 or VDAC1 overexpression in the subject to restore rhythmic contraction, 
 ii) inducing overexpression of
 VDAC2 or VDAC1 and/or 
 MCU or MICU1 complex, 
 
 iii) administering to the subject in need thereof an agent effective to activate
 VDAC2 or VDAC1 and/or 
 MCU or MICU1 complex, or 
 
 iv) administering to the subject in need thereof an agent effective to induce Ca2+ transporting activity of VDAC2 or VDAC1. 
 
     
     
         87 . The method of  claim 86 , wherein inducing VDAC2 or VDAC1 overexpression in the subject is via gene therapy. 
     
     
         88 . The method of  claim 86 , wherein the agent is a VDAC2 or VDAC1 gene product. 
     
     
         89 . The method of  claim 88 , wherein the VDAC2 or VDAC1 gene product is a VDAC2 or VDAC1 protein, or a VDAC2 or VDAC1 RNA. 
     
     
         90 . The method of  claim 86 , wherein the agent is the compound of Formula Ic. 
     
     
         91 . The method of  claim 90 , wherein the compound of Formula Ic is in an optically active form. 
     
     
         92 . The method of  claim 90 , wherein the agent is efsevin or a compound having the structure of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         93 . The method of  claim 92 , wherein the agent is an enantiomer of the agent. 
     
     
         94 . A method of forming the compound of Formula Ic: 
       
         
           
           
               
               
           
         
         where R 1  is substituted phenyl or substituted or unsubstituted heteroaryl; and R 2  is substituted phenyl or substituted or unsubstituted heteroaryl; and R 3  is R 3  is an alkoxy, amino, amino ether, N-Boc-protected 2-aminoethoxyethoxyethylamino group, or a C1-C10 straight or branched, acyclic or cyclic alkyloxy group, aryloxy, or amino group with or without heteroatom 
         comprising reacting 
       
       
         
           
           
               
               
           
         
       
       according to a reaction of Scheme III 
       
         
           
           
               
               
           
         
         to form the compound of Formula Ic. 
       
     
     
         95 . The method of  claim 94 , wherein the reaction of Scheme III is carried out under asymmetric synthesis conditions. 
     
     
         96 . The method of  claim 94 , wherein the compound of Formula Ic is formed in an optically active form.