Therapeutic compounds and methods of use

Abstract

The invention relates to protein binding interacting/binding compounds and methods of identifying and using them. The invention further relates to pharmaceutical compositions and methods for treating 5-HT2C disorders, including diseases and disorders mediated by GPCRs.

1 . A method of treating or preventing a GPCR-mediated disorder in a subject comprising administering to the subject identified as in need thereof a APT compound. 
   
   
       2 . The method of  claim 1 , wherein the APT compound is a compound of Table 1. 
   
   
       3 . The method of  claim 1 , wherein the APT compound is: 
     
       
         
         
             
             
         
       
     
     wherein,
 R 1  is independently H or optionally substituted phenyl (e.g., halo, alkoxy, CF 3 ); and 
 R 2  is independently H or optionally substituted phenyl (e.g., halo, alkoxy, CF 3 ); 
 or salt, hydrate or solvate thereof. 
 
   
   
       4 . The method of  claim 3 , wherein in the APT compound only one of R 1  and R 2  is H. 
   
   
       5 . The method of  claim 4 , wherein in the APT compound only one of R 1  and R 2  is optionally substituted phenyl. 
   
   
       6 . The method of  claim 1 , wherein the disorder is a neuropsychiatric disorder (e.g., obesity, addiction, anxiety, depression, schizophrenia, and sleep disorders), a neurodegenerative disorder (e.g., Parkinson's Disease, Alzheimer's Disease), a neurological disorder (e.g., epilepsy), a cardiovascular disorder (e.g., hypertension), a gastrointestinal disorder (e.g., irritable bowel syndrome), or a genitor-urinary tract disorder (e.g., bladder control). 
   
   
       7 . The method of  claim 1 , wherein the disorder is cocaine addiction. 
   
   
       8 . The method of  claim 1 , wherein the disorder is obesity. 
   
   
       9 . A method of inhibiting 5-HT2C in a subject identified as in need of such treatment, comprising administering a APT compound. 
   
   
       10 . A method of treating obesity in a subject comprising administering to the subject identified as in need thereof a APT compound capable of selectively inhibiting the 5-HT2c relative to 5-HT2a or 5-HT2b. 
   
   
       11 . The method of  claim 10 , wherein the binding interaction the for inhibiting 5-HT2c is at least 5-fold (alternatively at least 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 500 fold) greater than for either 5-HT2a or 5-HT2b. 
   
   
       12 . The method of  claim 10 , wherein the wherein the binding interaction the for inhibiting 5-HT2c is at least 100-fold greater than for either 5-HT2a or 5-HT2b. 
   
   
       13 . A method for identifying a compound that is capable of modulating 5-HT2c activity comprising; (i) producing a three-dimensional representation of a molecule or molecular complex, wherein said molecule or molecular complex comprises a binding pocket defined by structure coordinates of 5-HT2c; or b) a three-dimensional representation of a homologue of said molecule or molecular complex, wherein said homologue comprises a binding pocket that has a root mean square deviation from the backbone atoms of said amino acids of not more than about 2.0 angstroms; (ii) producing a three-dimensional representation of a test compound; (iii) assessing the binding interaction of the test compound with the target. 
   
   
       14 . The method of  claim 13 , further comprising contacting the test compound with a 5-HT2c and measuring the binding activity of the compound. 
   
   
       15 . A compound that is: 
     
       
         
         
             
             
         
       
     
     wherein,
 R 1  is independently H or optionally substituted phenyl (e.g., halo, alkoxy, CF 3 ); and 
 R 2  is independently H or optionally substituted phenyl (e.g., halo, alkoxy, CF 3 ); 
 
     or salt, hydrate or solvate thereof. 
   
   
       16 . The compound of  claim 15 , wherein R 1  and R 2  are not simultaneously the same. 
   
   
       17 . A composition comprising a compound of  claim 15  and a pharmaceutically acceptable carrier. 
   
   
       18 . A method of making a composition of  claim 17  comprising combining a compound of  claim 15  and a pharmaceutically acceptable carrier.