Compounds and Compositions for Treating Fibrosis

Abstract

The present invention provides compounds and methods for treating MKP-5 modulated disease. In certain embodiments, the MKP-5 modulated disease is a fibrotic disease.

What is claimed is: 
     
         1 . A method of treating, ameliorating, or preventing a MKP-5-modulated disease or disorder in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (1a) or (1b): 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is selected from the group consisting of NR, NC(═O)R, CH 2  and O and the   bond is single; or 
 Z is N and the   bond is double; 
 R 1  is selected from the group consisting of C 1 -C 6  alkyl, optionally substituted phenyl and NRR; 
 each occurrence of R is independently selected from the group consisting of H, C 1 -C 6  alkyl and optionally substituted phenyl; 
 A is selected from the group consisting of optionally substituted phenyl and optionally substituted heteroaryl. 
 
     
     
         2 . The method of  claim 1 , wherein the compound is the compound of formula (2): 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is selected from the group consisting of CH 2  and O; 
 R 1  is selected from the group consisting of C 1 -C 6  alkyl, optionally substituted phenyl and NRR, where each occurrence of R is independently selected from the group consisting of H, C 1 -C 3  alkyl and substituted or unsubstituted phenyl; 
 R 3  is selected from the group consisting of H, C 1 -C 6  alkyl, and C 1 -C 3  thioether; and 
 R 4  is selected from the group consisting of H and COORS, where R 5  is selected from the group consisting of H and C 1 -C 6  alkyl. 
 
     
     
         3 . The method of  claim 1 , wherein the aryl or heteroaryl is substituted with at least one substituent selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  thioalkyl, C(═O)OH, C(═O)OC 1 -C 6  alkyl, cyano and halo. 
     
     
         4 . The method of  claim 1 , wherein the compound has a Ki≤100 μM against MKP-5. 
     
     
         5 . The method of  claim 1 , wherein the compound binds to an allosteric site of MKP-5. 
     
     
         6 . The method of  claim 1 , wherein the compound is selected from the group consisting of 3,3-dimethyl-1-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one; 1-((5,6-dihydrobenzo[h]quinazolin-2-yl)thio)-3,3-dimethylbutan-2-one; N,N-dimethyl-2-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)acetamide; N-ethyl-N-methyl-2-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)acetamide; 1-((9-fluoro-5,6-dihydrobenzo[h]quinazolin-2-yl)thio)-3,3-dimethylbutan-2-one; 1-((6H-isochromeno[4,3-d]pyrimidin-2-yl)thio)-3,3-dimethylbutan-2-one; 1-(2,4-dichlorophenyl)-2-((4-(3,4-dimethylthieno[2,3-b]thiophen-2-yl)pyrimidin-2-yl)thio)ethan-1-one; 1-((5,6-dihydrothieno[2,3-h]quinazolin-2-yl)thio)-3,3-dimethylbutan-2-one; 3,3-dimethyl-1-(pyrimido[5,4-c]quinolin-2-ylthio)butan-2-one; and 1-((6-acetyl-5,6-dihydropyrimido[5,4-c]quinolin-2-yl)thio)-3,3-dimethylbutan-2-one; and 3,3-dimethyl-1-((9-propyl-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one. 
     
     
         7 . The method of  claim 1 , wherein the compound is selected from the group consisting of YU032149, HJ830, HJ845, HJ846, HJ858, and HJ862. 
     
     
         8 . The method of  claim 1 , wherein the compound is administered as part of a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier. 
     
     
         9 . The method of  claim 1 , wherein the MKP-5 modulated disease or disorder is a fibrotic disease or disorder. 
     
     
         10 . The method of  claim 9 , wherein the MKP-5 modulated disease or disorder is selected from the group consisting of dystrophic muscle disease, a cardiac or vascular disease, idiopathic pulmonary fibrosis, and any combinations thereof. 
     
     
         11 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         12 . The method of  claim 1 , wherein the MKP-5 inhibitor is administered to the mammal by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous routes. 
     
     
         13 . The method of  claim 1 , further comprising administering to the mammal at least one additional agent that treats or prevents the MKP-5 modulated disease or disorder in the mammal. 
     
     
         14 . The method of  claim 13 , wherein the inhibitor and at least one additional agent are coformulated. 
     
     
         15 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . A kit for preventing or treating a MKP-5 modulated disease or disorder in a mammal, the kit comprising a MKP-5 inhibitor, optionally an applicator, and an instructional material for use thereof, wherein the instructional material recites the amount of, and frequency with which, the MKP-5 inhibitor is to be administered to the mammal to treat or prevent the MKP-5 modulated disease or disorder. 
     
     
         17 . A method of determining if a test compound is a MKP-5 inhibitor, the method comprising:
 contacting a test compound with (i) a substrate peptide comprising the amino acid sequence pThr-Gly-pTyr and (ii) a catalytic polypeptide comprising and/or consisting of the catalytic domain of MKP-5, or an active fragment thereof, thus forming a composition;   measuring MKP-5 activity in the composition; and   comparing the MKP-5 activity in the composition to a control;   thereby determining if the test compound is a MKP-5 inhibitor.   
     
     
         18 . The method of  claim 17 , wherein the substrate peptide comprises the amino acid sequence Asp-Asp-Glu-Nle-pThr-Gly-pTyr-Val-Ala-Thr-Arg (pTpY, SEQ ID NO:3). 
     
     
         19 . The method of  claim 17 , wherein the measuring of MKP-5 activity comprises measuring any change in inorganic free phosphate in the composition.