Agents for preventing and treating disorders involving modulation of the ryanodine receptors

Abstract

Methods for reducing toxicity or side effects caused by administration of a rycal compound for repairing ryanodine receptor channel leaks when treating a disorder in a subject caused by such leaks. These methods are based upon the selection for administration of those rycal compounds having properties including an EC 50 value of 102 nM when assayed for its ability to facilitate the rebinding of FKBP12.6 to PKA-phosphorylated RyR2 or less and less than 50% inhibition of the hERG K + channel (I Kr ) when administered at 10 μM to reduce compound toxicity or side effects after administration compared to other rycal compounds not having those properties.

What is claimed is: 
     
         1 . in a method of treating a disorder in a subject caused by a ryanodine receptor channel leak by administering to the subject a therapeutically effective amount of a rycal compound to repair the channel leak to treat the disorder, the improvement which comprises selecting for administration a rycal compound having properties including an EC 50  value of 102 nM or less when assayed for its ability to facilitate the rebinding of FKBP12.6 to PKA-phosphorylated RyR2 and less than 50% inhibition of the hERG K +  channel (I Kr ) when administered at 10 μM to reduce compound toxicity or side effects after administration compared to other rycal compounds not having those properties. 
     
     
         2 . The method of  claim 1 , wherein the disorder is selected from the group consisting of cardiac disorders or diseases, skeletal muscular disorders or diseases, cognitive disorders or diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome. 
     
     
         3 . The method of  claim 2 , wherein the cardiac disorders and diseases are selected from the group consisting of irregular heartbeat disorders or diseases; exercise-induced irregular heartbeat disorders or diseases; heart failure, congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure; the skeletal muscular disorders or diseases are selected from the group consisting of skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence; and the cognitive disorders or diseases are selected from the group consisting of Alzheimer's Disease, forms of memory loss, and age-dependent memory loss. 
     
     
         4 . The method of  claim 1 , wherein the compound is a benzothiazepine compound. 
     
     
         5 . The compound of  claim 4 , wherein the benzothiazepine compound is a 1,4-benzothiazepine compound 
     
     
         6 . The compound of  claim 5 , having the formula: 
       
         
           
           
               
               
           
         
         wherein R′ and R″ are independently selected from the group consisting of H, halogen, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —N 3 , —SO 3 H, —S(═O) 2 alkyl, —OS(═O) 2 CF 3 , acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; and wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-) arylthio may be substituted or unsubstituted; 
         R 15  and R 16  independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, OH, NH 2 , alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted; optionally R 15  and R 16  together with the N to which they are bonded may form a heterocycle which may be substituted or unsubstituted; 
         R 17  is H, —NR 15 R 16 , —NHNR 15 R 16 , —NHOH, —CH 2 X, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted; and 
         n is 0, 1, or 2; 
         or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The compound of  claim 6 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 7 , wherein the benzodiazepine compound is S36, S57, S59, S76 or S107 or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound of  claim 6 , wherein R′ and R″ are independently selected from the group consisting of H, halogen, —OH, —OMe, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —N 3 , —S(═O) 2 C 1 -C 4 alkyl, —S(═O)C 1 -C 4 alkyl, —S—C 1 -C 4 alkyl, —OS(═O) 2 CF 3 , Ph, —NHCH 2 Ph, —C(C═O)Me, morpholinyl and propenyl; and n is 1 or 2. 
     
     
         10 . A method for reducing toxicity or side effects associated with treatment of a disorder in a subject caused by a ryanodine receptor channel teak, which comprises:
 identifying a rycal compound that has the ability when administered to the subject in a therapeutically effective amount to repair the channel leak to treat the disorder;   testing the compound to determine properties including EC 50  when assayed for its ability to facilitate the rebinding of FKBP12.6 to PKA-phosphorylated. RyR2 and hERG K +  channel (I Kr ) inhibition when administered at 10 μM; and   selecting for the treatment a rycal compound that has an EC 50  value of 102 or less and less than 50% inhibition of the hERG K +  channel (I Kr ) in order to reduce toxicity or side effects after administration compared to other rycal compounds not having those properties.   
     
     
         11 . The method of  claim 10 , wherein the disorder is selected from the group consisting of cardiac disorders or diseases, skeletal muscular disorders or diseases, cognitive disorders or diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome; 
     
     
         12 . The method of  claim 11 , wherein the cardiac disorders and diseases are selected from the group consisting of irregular heartbeat disorders or diseases; exercise-induced irregular heartbeat disorders or diseases; heart failure, congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure; the skeletal muscular disorders or diseases are selected from the group consisting of skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence; and the cognitive disorders or diseases are selected from the group consisting of Alzheimer's Disease, forms of memory loss, and age-dependent memory loss. 
     
     
         13 . The method of  claim 10 , wherein the compound is a benzothiazepine compound. 
     
     
         14 . The compound of  claim 13 , wherein the benzothiazepine compound is a 1,4-benzothiazine compound 
     
     
         15 . The compound of  claim 14 , having the formula: 
       
         
           
           
               
               
           
         
         wherein R′ and R″ are independently selected from the group consisting of H, halogen, —OH, —NH 2 , —NO 2 , —CN, —CF 3 , —OCF 3 , —N 3 , —SO 3 H, —S(═O) 2 alkyl, —OS(═O) 2 CF 3 , acyl, alkyl, alkoxyl, alkylamino, alkylthio, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-)arylthio, and (hetero-)arylamino; and wherein each acyl, alkyl, alkoxyl, alkylamino, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, (hetero-)aryl, (hetero-) arylthio may be substituted or unsubstituted; 
         R 15  and R 16  independently are selected from the group consisting of H, acyl, alkenyl, alkoxyl, OH, NH 2 , alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each acyl, alkenyl, alkoxyl, alkyl, alkylamino, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted; optionally R 15  and R 16  together with the N to which they are bonded may form a heterocycle which may be substituted or unsubstituted; 
         R 17  is H, —NR 15 R 16 , —NHNR 15 R 16 , —NHOH, —OR 15 , —CH 2 X, alkyl, alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; wherein each alkenyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be substituted or unsubstituted; and 
         n is 0, 1, or 2; 
         or an enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The compound of  claim 15 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 16 , wherein the benzodiazepine compound is S36, S57, S59, S76 or S107 or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 15 , wherein R′ and R″ are independently selected from the group consisting of H, halogen, —OH, —OMe, —NH 2 , —NO 2 , —CN, —OCF 3 , —N 3 , —S(═O) 2 C 1 -C 4 alkyl, —S(═O)C 1 -C 4 alkyl, —S—C 1 -C 4 alkyl, —OS(═O) 2 CF 3 , Ph, —NHCH 2 Ph, morpholinyl and propenyl; and n is 1 or 2.