Novel rexinoid compounds and methods of using rexinoid compounds for treating metabolic disorders and cancer

Abstract

Novel rexinoid compounds are provided herein. Also provided herein are methods of using the compounds to treat disorders, such as metabolic disorders, diabetes, insulin resistance, glucose intolerance, obesity, steatosis, inflammation, and/or cancer.

1 . A compound of the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
         m is 0-4, n is 0-3, and p is 0-2; 
         R is selected from the group consisting of H, alkyl, benzyl, aryl, or heteroaryl; 
         each R 1 , R 2 , and R 3  are independently selected from the group consisting of H, halo, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, aryl, OR 4 , NH 2 , NHR 4 , NR 4 R 5 , and SR 4 , where R 4  and R 5  are each independently selected from H, C 1 -C 6  alkyl, and —C(O)R 6 , where R 6  is H, C 1 -C 6  alkyl, or aryl; 
         X and Y are each independently selected from the group consisting of C—H, C—(C 1 -C 6  alkyl), N, O, and S, wherein when X is O or S, then Y is absent such that a five-membered heteroaromatic ring is formed or when Y is O or S, then X is absent such that a five-membered heteroaromatic ring is formed; and 
         A, B, C and D are each independently selected from the group consisting of —CH 2 —, —CHF—, —CF 2 —, —CHCl—, —CCl 2 —, —CHBr—, —CBr 2 —, —CH(C 1 -C 6  alkyl)-, —C(C 1 -C 6  alkyl) 2 -, —CH (C 1 -C 6  haloalkyl)-, —C (C 1 -C 6  haloalkyl) 2 -, —CH═CH—, —C(R 5 )═CH—, —CH═C(R 5 )—, —C(R 5 )═CR—, and —C or one or more of A, B, C, or D is absent such that the remaining units connect to form a chain. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . (canceled) 
     
     
         11 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         12 - 18 . (canceled) 
     
     
         19 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         20 . A method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject an effective amount of a compound of  claim 1 . 
     
     
         21 . The method of  claim 20 , wherein administering the compound provides a glucose-lowering effect, an insulin-sensitizing effect, or a plasma triglyceride lowering effect. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . A method of treating or preventing insulin resistance, glucose intolerance, obesity, steatosis or inflammation in a subject, comprising administrating to a subject in thereof an effective amount of a compound of  claim 1 . 
     
     
         25 . The method of  claim 20 , wherein the subject is a rodent or human, obese, morbidly obese, pre-diabetic, or diabetic. 
     
     
         26 - 29 . (canceled) 
     
     
         30 . The method of  claim 20 , wherein the compound is administered orally, topically, intranasally, intravenously, subcutaneously, intradermally, transdermally intramucosally intramuscularly, by inhalation spray, rectally, nasally, sublingually, buccally, vaginally or via an implanted reservoir. 
     
     
         31 . (canceled) 
     
     
         32 . A method of treating or preventing cancer in a subject, comprising administering to a subject an effective amount of a compound of  claim 1 . 
     
     
         33 - 36 . (canceled) 
     
     
         37 . A kit for treating a metabolic disorder, insulin resistance, glucose intolerance, obesity, steatosis, inflammation, or cancer, wherein the kit comprises:
 a compound of  claim 1 ; and   a container including the compound.   
     
     
         38 . A kit for treating or preventing cancer, wherein the kit comprises:
 a compound of  claim 1 ; and   a container including the compound.   
     
     
         39 . (canceled) 
     
     
         40 . A method of treating diabetes or a diabetes complication in a subject, comprising administering to a subject an effective amount of a compound of  claim 1 .