Peripherally restricted gaba positive allosteric modulators for the treatment of irritable bowel syndrome and other ailments of the peripheral nervous system

Abstract

The present invention provides compounds and compositions which are positive allosteric modulators of GABA-A receptors that selectively target the peripheral nervous system and organs of the body, and which do not pass through the blood-brain barrier. The compounds and compositions of the present invention are useful for treatment of diseases or disorders which are mediated by GABA-A neuronal activity, such as, for example, visceral pain, gut motility, irritable bowel syndrome, functional abdominal pain, functional idiopathic diarrhea, inflammatory bowel diseases, drug induced pain, bile salt malabsorption, lactase or other carbohydrate intolerance.

1 . A method for suppressing neuronal excitability in tissues and organs outside of the brain and central nervous system, the method comprising administering to a subject in need of such suppressing a therapeutically effective amount of a peripherally-restricted GABA-A receptor positive allosteric modulator. 
     
     
         2 . The method of  claim 1 , wherein neuronal excitability is GABAergic neuronal excitability in tissues and organs outside of the brain and central nervous system. 
     
     
         3 . The method of  claim 1 , wherein suppressing neuronal excitability in tissues and organs outside of the brain and central nervous system comprises positively modulating GABA-A receptors in tissues and organs outside the brain and central nervous system. 
     
     
         4 . The method of  claim 1 , wherein the peripherally-restricted GABA-A receptor positive allosteric modulator does not substantially cross an intact blood brain barrier of the subject. 
     
     
         5 . The method of  claim 1 , wherein less than 50% of the peripherally-restricted GABA-A receptor positive allosteric modulator crosses an intact blood brain barrier of the subject. 
     
     
         6 . The method of  claim 1 , wherein less than 40% of the peripherally-restricted GABA-A receptor positive allosteric modulator crosses an intact blood brain barrier of the subject. 
     
     
         7 . The method of  claim 1 , wherein less than 30% of the peripherally-restricted GABA-A receptor positive allosteric modulator crosses an intact blood brain barrier of the subject. 
     
     
         8 . The method of  claim 1 , wherein less than 20% of the peripherally-restricted GABA-A receptor positive allosteric modulator crosses an intact blood brain barrier of the subject. 
     
     
         9 . The method of  claim 1 , wherein less than 10% of the peripherally-restricted GABA-A receptor positive allosteric modulator crosses an intact blood brain barrier of the subject. 
     
     
         10 . The method of  claim 1 , wherein less than 5% of the peripherally-restricted GABA-A receptor positive allosteric modulator crosses an intact blood brain barrier of the subject. 
     
     
         11 . The method of  claim 1 , wherein less than 1% of the peripherally-restricted GABA-A receptor positive allosteric modulator crosses an intact blood brain barrier of the subject. 
     
     
         12 . The method of  claim 1 , wherein less than 0.5% of the peripherally-restricted GABA-A receptor positive allosteric modulator crosses an intact blood brain barrier of the subject. 
     
     
         13 . The method of  claim 1 , wherein less than 0.1% of the peripherally-restricted GABA-A receptor positive allosteric modulator crosses an intact blood brain barrier of the subject. 
     
     
         14 . The method of  claim 1 , wherein the ratio of a concentration of the peripherally-restricted GABA-A receptor positive allosteric modulator in the brain to a concentration of the peripherally-restricted GABA-A receptor positive allosteric modulator in the circulating plasma is about 1:5. 
     
     
         15 . The method of  claim 1 , wherein the ratio of a concentration of the peripherally-restricted GABA-A receptor positive allosteric modulator in the brain to a concentration of the peripherally-restricted GABA-A receptor positive allosteric modulator in the circulating plasma is about 1:10. 
     
     
         16 . The method of  claim 1 , wherein the average concentration of the peripherally-restricted GABA-A receptor positive allosteric modulator in the brain is less than 62.5 nM. 
     
     
         17 . The method of  claim 1 , wherein the peripherally-restricted GABA-A receptor positive allosteric modulator binds to the GABA-A receptor with a Ki of less than 500 nM. 
     
     
         18 . The method of  claim 1 , wherein upon administration of the peripherally-restricted GABA-A receptor positive allosteric modulator the subject does not experience unwanted sedation side effects. 
     
     
         19 . The method of  claim 1 , wherein the peripherally-restricted GABA-A receptor positive allosteric modulator is a compound having formulas 1 or 2: 
       
         
           
           
               
               
           
         
         wherein, A 1 , A 2 , and A 3  are independently selected from C or N, where at least one of A 1 , A 2 , or A3 is a C unsubstituted or substituted with a group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —COOR 10 , —COR 10 , —OR 10 , —SR 10 , —NR 10 R 11 , and —CONR 10 R 11 ; 
         each of R 10  and R 11  is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl optionally substituted with one or more amidinyl, guanidinyl, phosphate, sulfate, tetrazole, 3-hydroxyisoxazole, quaternary ammonium salts including urea, primary amides, sulfonamides, sulfonyl ureas, acylamidines, acylguanidines, or —NR 12 R 13  groups; 
         each of R 12  and R 13  is independently H, —CONH 2 , —SOONH 2 , alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; 
         X is O; 
         Y is selected from H, OH, OQ, and CO 2 Q where Q is a prodrug that liberates Y=H or Y=OH; 
         Z is selected from oxygen and an electron lone pair; 
         R 1  is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl optionally substituted with one or more halo, CF 3 , CN, NO 2 , COOH, C 1-4  alkyl, C 2-4  alkenyl, C 1-4  alkynyl, OH, OR (where OR is C 1-4  alkyl or C 1-4  fluoroalkyl), SO 2 R (where R is C 1-4  alkyl or C 1-4  fluoroalkyl); 
         R 5  is selected from the group consisting of aryl, heteroaryl, or cycloalkenyl groups optionally substituted with one or more halo, CF 3 , CN, NO 2 , C 1-4  alkyl, C 2-4  alkenyl, C 1-4  alkynyl, OH, OR (where OR is C 1-4  alkyl or C 1-4  fluoroalkyl), and SO 2 R (where R is C 1-4  alkyl or C 1-4  fluoroalkyl); and 
         R 6 , R 7 , R 8 , R 9  are each independently selected from the group consisting of H, halo, CF 3 , CN, NO 2 , C 1-4  alkyl, C 2-4  alkenyl, C 1-4  alkynyl, OH, OR (where OR is C 1-4  alkyl or C 1-4  fluoroalkyl), and SO 2 R (where R is C 1-4  alkyl or C 1-4  fluoroalkyl) compounds; or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . The method of  claim 19 , wherein the peripherally-restricted GABA-A receptor positive allosteric modulator is a pharmaceutically acceptable salt of the compound of formula 1 or 2. 
     
     
         21 . The method of  claim 19 , wherein the peripherally-restricted GABA-A receptor positive allosteric modulator is a compound of formula 1. 
     
     
         22 . The method of  claim 21 , wherein the peripherally-restricted GABA-A receptor positive allosteric modulator is a pharmaceutically acceptable salt of the compound of formula 1. 
     
     
         23 . The method of  claim 1 , wherein the peripherally-restricted GABA-A receptor positive allosteric modulator is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method of  claim 23 , wherein the peripherally-restricted GABA-A receptor positive allosteric modulator is a pharmaceutically acceptable salt of the compound of  claim 23 . 
     
     
         25 . The method of  claim 1 , wherein the method further comprises administering the peripherally-restricted GABA-A receptor positive allosteric modulator as a pharmaceutical composition comprising the peripherally-restricted GABA-A receptor positive allosteric modulator and a pharmaceutically acceptable carrier. 
     
     
         26 . The method of  claim 1 , wherein the method further comprises administering at least one additional therapeutic agent. 
     
     
         27 . The method of  claim 1 , wherein the method further comprises administering at least one additional therapeutic agent for positive modulation of GABA-A receptors in tissues and organs outside the brain.