Hydrazide-containing cftr inhibitor compounds and uses thereof

Abstract

The invention provides compositions, pharmaceutical preparations and methods for inhibition of cystic fibrosis transmembrane conductance regulator protein (CFTR) that are useful for the study and treatment of CFTR-mediated diseases and conditions. The compositions and pharmaceutical preparations of the invention may comprise one or more hydrazide-containing compounds, and may additionally comprise one or more pharmaceutically acceptable carriers, excipients and/or adjuvants. The methods of the invention comprise, in certain embodiments, administering to a patient suffering from a CFTR-mediated disease or condition, an efficacious amount of a hydrazide-containing compound. In other embodiments the invention provides methods of inhibiting CFTR that comprise contacting cells in a subject with an effective amount of a hydrazide-containing compound. In addition, the invention features a non-human animal model of CFTR-mediated disease which model is produced by administration of a hydrazide-containing compound to a non-human animal in an amount sufficient to inhibit CFTR.

1 . A compound having the structure of formula (Ic): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, 
         wherein Y is hydrogen or a substituted or unsubstituted, saturated linear or branched alkyl; 
         R 1  is
 unsubstituted phenyl, 
 substituted phenyl wherein phenyl is substituted with one or more of hydroxy, alkyl and halogen, 
 substituted or unsubstituted anthracenyl, or 
 substituted or unsubstituted naphthalenyl; 
 
         R 2  is unsubstituted phenyl,
 substituted phenyl, wherein phenyl is substituted with bromo or carboxy, 
 di(hydroxy)phenyl, 
 mono(halo)-mono(hydroxy)phenyl, 
 mono(halo)-di(hydroxy)phenyl, 
 mono(halo)-tri(hydroxy)phenyl, 
 di(halo)-mono(hydroxy)phenyl, 
 di(halo)-di(hydroxy)phenyl, 
 di(halo)-tri(hydroxy)phenyl, 
 mono(halo)-mono(hydroxy)-mono(alkoxy)phenyl, 
 mono(halo)-di(hydroxy)-mono(alkoxy)phenyl, 
 mono(halo)-mono(hydroxy)-di(alkoxy)phenyl, 
 mono(halo)-di(hydroxy)-di(alkoxy)phenyl, 
 di(halo)-mono(hydroxy)-mono(alkoxy)phenyl, 
 di(halo)-di(hydroxy)-mono(alkoxy)phenyl, 
 di(halo)-mono(hydroxy)-di(alkoxy)phenyl; and 
 
         R 3  is hydrogen or substituted or unsubstituted alkyl. 
       
     
     
         2 . The method of  claim 1 , wherein R 1  is substituted or unsubstituted 1-naphthalenyl, substituted or unsubstituted 2-naphthalenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-methylphenyl, or 2-anthracenyl. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is mono-(halo)phenyl; mono-(alkyl)phenyl; mono-(halo)napthalenyl; di-(halo)napthalenyl; mono-(hydroxy)napthalenyl; di-(hydroxy)napthalenyl; mono-(alkoxy)napthalenyl; di-(alkoxy)naphthalenyl; tri-(alkoxy)naphthalenyl; mono-(alkyl)naphthalenyl; di-(alkyl)napthalenyl; mono-(hydroxyl)-mono(sulfo)napthalenyl; mono-(hydroxy)-di(sulfo)napthalenyl; mono-(alkyl)-mono-(alkoxy)-napthalenyl; or mono-(alkyl)-di-(alkoxy)-napthalenyl. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is a 2-naphthalenyl group. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is 3,5-dibromo-2,4-dihydroxyphenyl; 3,5-dibromo-2,4,6-trihydroxyphenyl; 3,5-dibromo-4-hydroxyphenyl; 3,5dibromo-2-dihydroxy-4-methoxyphenyl; 3-bromo-4-hydroxyphenyl; 2,4-dihydroxyphenyl; or 4-bromophenyl. 
     
     
         6 . The compound of  claim 1 , wherein R 2  is chosen from a 3,5-dibromo-2,4-dihydroxyphenyl or a 3,5-dibromo-4-hydroxyphenyl group. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is chosen from hydrogen, methyl group, or ethyl. 
     
     
         8 . The compound of  claim 1 , wherein R 3  is hydrogen or methyl. 
     
     
         9 . The compound of  claim 1 , wherein Y is a substituted alkyl group comprising a sulfo group, a carboxy group, a substituted or unsubstituted carboxamide group, a polyoxyalkylether group, a disaccharide, a polyamine, a substituted or unsubstituted phenyl group, a polyethyleneimine (PEI), or a dendrimer from 0-10 generation. 
     
     
         10 . The compound of  claim 1 , wherein Y is C 1 -C 8  alkyl. 
     
     
         11 . The compound of  claim 1 , wherein Y is hydrogen; R 1  is mono-(halo)phenyl or naphthalenyl; R 2  is di-(halo)-mono-(hydroxy)phenyl or di-(halo)-di-(hydroxy)phenyl; and R 3  is hydrogen or methyl. 
     
     
         12 . The compound of  claim 1 , wherein the compound of formula (Ic) has the following structure selected from: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         14 . A method for inhibiting cystic fibrosis transmembrane conductance regulator (CFTR) ion transport in a cell, the method comprising contacting the cell with the compound of  claim 1 . 
     
     
         15 . The method of  claim 14 , wherein the cell is in a subject who has aberrantly increased intestinal secretion. 
     
     
         16 . The method of  claim 15 , wherein the aberrantly increased intestinal secretion is secretory diarrhea. 
     
     
         17 . The method of  claim 14 , wherein the cell is in a subject who has polycystic kidney disease. 
     
     
         18 . A method for inhibiting the activity of cystic fibrosis transmembrane conductance regulator (CFTR) protein in a cell in an in vitro assay, comprising contacting the cell with the compound of  claim 1  in an amount effective to inhibit CFTR activity. 
     
     
         19 . A method for producing a cystic fibrosis (CF) phenotype in a non-human animal, wherein the method comprises administering to the non-human animal the compound of  claim 1  in an amount effective to inhibit CFTR ion transport. 
     
     
         20 . A non-human animal having a cystic fibrosis transmembrane conductance regulator (CFTR) deficiency produced by the method of  claim 19 , wherein the deficiency is produced by administration of the hydrazide-containing compound to the animal.