Reverse-turn mimetics and method relating thereto

Abstract

Conformationally constrained compounds that mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins are disclosed. Such reverse-turn mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the reverse-turn mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members. The invention also relates to the use of such compounds for inhibiting or treating disorders modulated by Wnt-signaling pathway, such as cancer, especially colorectal cancer, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, rheumatoid arthritis disease, tuberous sclerosis complex, Alzheimer's disease, excess hair growth or loss, or ulcerative colitis.

1 - 42 . (canceled) 
     
     
         43 . A compound having the following general formula (III): 
       
         
           
           
               
               
           
         
         wherein W is —Y(C═O)—, —(C═O)NH—, —(SO 2 )— or nothing; Y is oxygen, sulfur or —NH—; X and Z are nitrogen or CH, wherein when Z is CH, then X is nitrogen; R 1 , R 2 , R 4 , R 6 , and R 9  are the same or different and independently selected from an amino acid side chain moiety or derivative thereof, as an isolated stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt. 
       
     
     
         44 . The compound of  claim 43 , wherein R 1 , R 2 , R 4 , R 6 , and R 9  are independently selected from the group consisting of aminoC 2-5 alkyl, guanidinoC 2-5 alkyl, C 1-4 alkylguanidinoC 2-5 alkyl, diC 1-4 alkylguanidino-C 2-5 alkyl, amidinoC 2-5 alkyl, C 1-4 alkylamidinoC 2-5 alkyl, diC 1-4 alkylamidinoC 2-5 alkyl, C 1-3 alkoxy, phenyl, substituted phenyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), benzyl, substituted benzyl (where the substituents on the benzyl are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), naphthyl, substituted naphthyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4  alkylamino, C 1-4  dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4  alkylamino, C 1-4  dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyridyl, substituted pyridyl, (where the substituents are independently selected from one or more of amino amidino, guanidino, hydrazino, amidazonyl, C 1-4  alkylamino, C 1-4  dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyridylC 1-4 alkyl, substituted pyridylC 1-4 alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4  dialkylamino, halogen, perfluoro C 1-4  alkyl, C 1-4  alkyl, C 1-3  alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), pyrimidylC 1-4 alkyl, substituted pyrimidylC 1-4 alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy or nitro, carboxy, cyano, sulfuryl or hydroxyl), triazin-2-yl-C 1-4 -alkyl, substituted triazin-2-yl-C 1-4 alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4  dialkylamino, halogen, perfluoro C 1-4  alkyl, C 1-4  alkyl, C 1-3  alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), imidazoC 1-4 alkyl, substituted imidazol C 1-4 alkl (where the imidazole substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidazonyl, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-4 alkyl, C 1-3 alkoxy, nitro, carboxy, cyano, sulfuryl or hydroxyl), imidazolinylC 1-4 alkyl, N-amidinopiperazinyl-N—C 0-4 alkyl, hydroxyC 2-5  alkyl, C 1-5  alkylamino C 2-5  alkyl, hydroxyC 2-5  alkyl, C 1-5  alkylaminoC 2-5  alkyl, C 1-5  dialkylaminoC 2-5  alkyl, N-amidinopiperidinylC 1-4  alkyl and 4-aminocyclohexylC 0-2 alkyl. 
     
     
         45 . A pharmaceutical composition comprising a compound according to  claim 43 . 
     
     
         46 . A pharmaceutical composition comprising a compound according to  claim 44 . 
     
     
         47 . A method for inhibiting tumor growth comprising administering to a patient in need thereof an effective amount of the compound according to  claim 43 . 
     
     
         48 . A method for inhibiting tumor growth comprising administering to a patient in need thereof.