Lpa receptor agonists and antagonists and methods of use

Abstract

Disclosed are compounds according to formula (I) as well as pharmaceutical compositions which include those compounds. Also disclosed are methods of using such compounds, which have activity as agonists or as antagonists of LPA receptors; such methods including inhibiting LPA activity on an LPA receptor, modulating LPA receptor activity, treating cancer, enhancing cell proliferation, treating a wound, treating apoptosis or preserving or restoring function in a cell, tissue, or organ, culturing cells, preserving organ or tissue function, and treating a dermatological condition.

1 . A method for treating diarrhea in a human or animal subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein,
 X 1  is R 1 —Y 1 -A-; 
 X 2  is —Z 1 —P(S)(OH) 2 ; 
 X 3  is hydrogen; 
 A is a direct link, (CH 2 ) k  with k being an integer from 1-30, or O; 
 Y 1  is (CH 2 ) l  with l being an integer from 1-30; 
 Z 1  is —O—; 
 Q 1  and Q 2  are independently selected from the group consisting of H 2 , ═NR 4 , ═O, or —NR 5 R 6 ; 
 R 1  is independently a straight or branched-chain C 2  to C 30  alkenyl, an aromatic or heteroaromatic ring with or without mono-, di-, or tri-substitutions of the ring, an acyl group substituted by a C 1  to C 30  alkyl oran aromatic or heteroaromatic ring, an arylalkyl including straight or branched-chain C 1  to C 30  alkyl, an aryloxyalkyl including straight or branched-chain C 1  to C 30  alkyl, 
 
       
         
           
           
               
               
           
         
       
       and
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are independently hydrogen, a straight or branched-chain C 1  to C 30  alkyl, a straight or branched-chain C 2  to C 30  alkenyl, an aromatic or heteroaromatic ring with or without mono-, di-, or tri-substitutions of the ring, an acyl including a C 1  to C 30  alkyl or aromatic or heteroaromatic ring, an arylalkyl including straight or branched-chain C 1  to C 30  alkyl, or an aryloxyalkyl including straight or branched-chain C 1  to C 30  alkyl. 
 
     
     
         2 . The method of  claim 1  wherein Q 1  and Q 2  of the compound of formula (I) are both hydrogen. 
     
     
         3 . The method of  claim 2  wherein R 1  of the compound of formula (I) is a C3 to C21 alkenyl. 
     
     
         4 . The method of  claim 2  wherein R 1  of the compound of formula (I) is a C7 to C21 alkenyl. 
     
     
         5 . The method of  claim 1  wherein the compound of formula (I) is selected from the group consisting of thiophosphoric acid, O-dec-9-enyl ester; thiophosphoric acid O-dodec-9-enyl ester; thiophosphoric acid O-tetradec-9-enyl ester; and thiophosphoric acid O-octadec-9-enyl ester. 
     
     
         6 . The method of  claim 1  wherein Q 1  and Q 2  of the compound of formula (I) are both H 2 , with A being a direct link and Y 1  being —(CH 2 ) l — with l being an integer from 1 to 30. 
     
     
         7 . The method of  claim 6  wherein R 1  of the compound of formula (I) is an alkyl-phenyl group. 
     
     
         8 . The method of  claim 7  wherein the compound of formula (I) is thiophosphoric acid O-[7-(4-octyl-phenyl)-heptyl]ester.