Non-steroidal farnesoid X receptor modulators and methods for the use thereof

Abstract

The efficient regulation of cholesterol synthesis, metabolism, acquisition, and transport is an essential component of lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of cholesterol metabolism. Accordingly, the development of potent, selective, small molecule agonists, partial agonists, and antagonists of FXR would be an important step in further deconvoluting FXR physiology. In accordance with the present invention, the identification of novel potent FXR activators is described. Two derivatives of invention compounds, bearing stilbene or biaryl moieties, contain members that are the most potent FXR agonists reported to date in cell-based assays. These compounds are useful as chemical tools to further define the physiological role of FXR as well as therapeutic leads for the treatment of diseases linked to cholesterol, bile acids and their metabolism and homeostasis.

1 . A compound having the structure:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is a C3 up to C8 branched chain alkyl or substituted alkyl group, a C3 up to C7 cycloalkyl or substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl,  
 X is —C(O)— or —CH 2 —,  
 R is methyl or ethyl,  
 R 1  is H, hydroxy, alkoxy, benzoyloxy, mesityloxy, or —OCH 2 C(O)OC 2 H 5 ,  
 R 2  is H or R 2  can cooperate with R 3  to form a benzopyran, wherein the pyran ring has the structure:  
                     
  wherein: 
 R 6  is not present if the pyran ring is unsaturated, or, if present, is selected from H, —OR, wherein R is alkyl or acyl, or R 6  can cooperate with R 7  to form a cyclic acetal, a cyclic ketal, or a cyclopropyl moiety, and  
 only one of R 7  and R 8  is present if the pyran ring is unsaturated, or R 7  and R 8  are independently H, carboxyl, cyano, hydroxy, alkoxy, thioalkyl, aryl, or R 7  and R 8  taken together comprise a carbonyl oxygen or an oxime nitrogen, or either R 7  or R 8  can cooperate with R 6  to form a cyclic acetal, a cyclic ketal, or a cyclopropyl moiety,  
 
 R 3  can cooperate with R 2  to form a benzopyran having the structure set forth above, or R 3  is alkenyl, optionally substituted aryl or heteroaryl, or optionally substituted arylalkenyl or heteroarylalkenyl,  
 R 4  is H or hydroxy, and  
 R 5  is H, hydroxy, alkoxy or aryloxy.  
 
     
     
         2 . The compound of  claim 1  wherein R 2  and R 3  cooperate to form a benzopyran.  
     
     
         3 . The compound of  claim 2  wherein A is cyclopropyl, X is —C(O)—, R 1  is methoxy, R 6  and R 7  are absent, and R 4 , R 5  and R 8  are hydrogen.  
     
     
         4 . The compound of  claim 2  wherein A is cyclopropyl, X is —CH 2 —, R 1  is methoxy, R 6  and R 7  are absent, and R 4 , R 5  and R 8  are hydrogen.  
     
     
         5 . The compound of  claim 2  wherein A is cyclohexyl, X is —C(O)—, R 1  is methoxy, R 6  and R 7  are absent, and R 4 , R 5  and R 8  are hydrogen.  
     
     
         6 . The compound of  claim 2  wherein A is phenyl, X is —C(O)—, R 1  is methoxy, R 6  and R 7  are absent, and R 4 , R 5  and R 8  are hydrogen.  
     
     
         7 . The compound of  claim 2  wherein A is phenyl, X is —C(O)—, R 1  is methoxy, R 6  and R 7  cooperate to form a dichlorocyclopropyl ring, and R 4 , R 5  and R 8  are hydrogen.  
     
     
         8 . The compound of  claim 2  wherein A is cyclohexyl, X is —C(O)—, R 1  is methoxy, R 6  and R 7  cooperate to form a dichlorocyclopropyl ring, and R 4 , R 5  and R 8  are hydrogen.  
     
     
         9 . The compound of  claim 1  wherein R 3  is alkenyl.  
     
     
         10 . The compound of  claim 9  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH—C(O)—O-tBu.  
     
     
         11 . The compound of  claim 1  wherein R 3  is optionally substituted aryl or heteroaryl.  
     
     
         12 . The compound of  claim 11  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is phenyl.  
     
     
         13 . The compound of  claim 11  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is p-thiomethyl-phenyl.  
     
     
         14 . The compound of  claim 11  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is m-methoxy-phenyl.  
     
     
         15 . The compound of  claim 11  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is m-acetyl-phenyl.  
     
     
         16 . The compound of  claim 11  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is 5-methyl-2-thiophene-yl.  
     
     
         17 . The compound of  claim 11  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is 5-acetyl-2-thiophene-yl.  
     
     
         18 . The compound of  claim 11  wherein A is cyclohexyl, X is —C(O)—, R 1  R 1 , R 4  and R 5  are hydrogen, and R 3  is 4-dimethylamino-phenyl.  
     
     
         19 . The compound of  claim 11  wherein A is isopropyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is 4-dimethylamino-phenyl.  
     
     
         20 . The compound of  claim 11  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is 2,3-(O—CH 2 —O)-phenyl.  
     
     
         21 . The compound of  claim 11  wherein A is isopropyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is 2,3-(O—CH 2 —O)-phenyl.  
     
     
         22 . The compound of  claim 1  wherein R 3  is or optionally substituted arylalkenyl or heteroarylalkenyl.  
     
     
         23 . The compound of  claim 22  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH-phenyl.  
     
     
         24 . The compound of  claim 22  wherein A is isopropyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH-phenyl.  
     
     
         25 . The compound of  claim 22  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH-p-methoxy-phenyl.  
     
     
         26 . The compound of  claim 22  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH-o-fluoro-phenyl.  
     
     
         27 . The compound of  claim 22  wherein A is isopropyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH-o-fluoro-phenyl.  
     
     
         28 . The compound of  claim 22  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH-m-fluoro-phenyl.  
     
     
         29 . The compound of  claim 22  wherein A is isopropyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH-m-fluoro-phenyl.  
     
     
         30 . The compound of  claim 22  wherein A is cyclohexyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH-p-fluoro-phenyl.  
     
     
         31 . The compound of  claim 22  wherein A is isopropyl, X is —C(O)—, R 1  R 2 , R 4  and R 5  are hydrogen, and R 3  is —CH═CH-p-fluoro-phenyl.  
     
     
         32 . A formulation comprising at least one compound according to  claim 1  in a pharmaceutically acceptable carrier therefor.  
     
     
         33 . A method for modulating process(es) mediated by farnesoid X receptor polypeptides, said method comprising conducting said process(es) in the presence of an effective amount of at least one compound according to  claim 1 .  
     
     
         34 . The method of  claim 33  wherein said process mediated by famesoid X receptor is cholesterol metabolism.  
     
     
         35 . The method of  claim 33  wherein said process mediated by famesoid X receptor is the regulation of lipid homeostasis.  
     
     
         36 . A method for the treatment of hypercholestemia, said method comprising administering an effective amount of at least one compound according to  claim 1  to a subject in need thereof.  
     
     
         37 . A method for the treatment of cholestasis, said method comprising administering an effective amount of at least one compound according to  claim 1  to a subject in need thereof.