Compounds Having Activity in Increasing Ion Transport by Mutant-CFTR and Uses Thereof

Abstract

The invention provides compositions, pharmaceutical preparations and methods for increasing activity (e.g., ion transport) of the mutant cystic fibrosis transmembrane conductance regulator protein (mutant-CFTR), e.g., DF508 CFTR, G551D-CFTR, G1349D-CFTR, or D1152H-CFTR, that are useful for the treatment of cystic fibrosis (CF). The compositions and pharmaceutical preparations of the invention may comprise one or more phenylglycine-containing compounds or sulfonamide-containing compounds of the invention, or an analog or derivative thereof.

1 .- 23 . (canceled) 
     
     
         24 . A method of treating a subject having a condition associated with mutant-CFTR, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
         where n R1 is independently chosen from a substituted or unsubstituted phenyl group, a substituted or unsubstituted heteroaromatic group, or a cyclic or acyclic alkyl group; R2 is independently chosen form a hydrogen, a alkyl group, an ether group, a halogen, or a perfluoroalkyl group; R3 is independently chosen from a hydrogen or an alkyl group, and R4 is independently chosen from a substituted or unsubstituted heteroaromatic group, or a alkanoyl-amine group; or a pharmaceutically acceptable derivative thereof, as an individual stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . The method of  claim 24 , wherein said condition is cystic fibrosis. 
     
     
         26 . The method of  claim 24 , wherein the subject, after treatment, has a decrease in mucous or bacterial titer in their lungs, a decrease in coughing or wheezing, a decrease in pancreatic insufficiency, or a decrease in electrolyte levels in their sweat. 
     
     
         27 . The method of  claim 24 , wherein said subject is a non-human animal. 
     
     
         28 . The method of  claim 24 , wherein the animal is a mammal. 
     
     
         29 . The method of  claim 24 , wherein the mutant-CFTR is a gating defective mutant-CFTR. 
     
     
         30 . The method of  claim 29 , wherein the gating defective mutant-CFTR is ΔF508-CFTR, G551D-CFTR, G1349D-CFTR, or D1152H-CFTR. 
     
     
         31 . A method of increasing ion permeability of a cell producing a mutant-CFTR protein, said method comprising contacting said cell with a compound of formula (I): 
       
         
           
           
               
               
           
         
         where n R1 is independently chosen from a substituted or unsubstituted phenyl group, a substituted or unsubstituted heteroaromatic group, or a cyclic or acyclic alkyl group; R2 is independently chosen form a hydrogen, a alkyl group, an ether group, a halogen, or a perfluoroalkyl group; R3 is independently chosen from a hydrogen or an alkyl group, and R4 is independently chosen from a substituted or unsubstituted heteroaromatic group, or a alkanoyl-amine group; or a pharmaceutically acceptable derivative thereof, as an individual stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof, 
         wherein said compound is provided in an amount effective to increase ion permeability of said cell. 
       
     
     
         32 . The method of  claim 31 , wherein said cell contains a recombinant expression cassette that encodes said mutant-CFTR protein. 
     
     
         33 . The method of  claim 31 , wherein said cell contains a genome that encodes said mutant-CFTR protein. 
     
     
         34 . The method of  claim 31 , wherein said ion permeability increases an ion transporting activity that increases a rate of transport of ions across the plasma membrane of said cell. 
     
     
         35 . The method of  claim 31 , wherein the mutant-CFTR is a gating defective mutant-CFTR. 
     
     
         36 . The method of  claim 35 , wherein the gating defective mutant-CFTR is ΔF508-CFTR, G551D-CFTR, G1349D-CFTR, or D1152H-CFTR. 
     
     
         37 . A method of treating a subject having cystic fibrosis, the method comprising:
 identifying a mutant-CFTR in the subject; and   administering to the subject a pharmaceutical composition comprising a compound of formula (I):   
       
         
           
           
               
               
           
         
         where n R1 is independently chosen from a substituted or unsubstituted phenyl group, a substituted or unsubstituted heteroaromatic group, or a cyclic or acyclic alkyl group; R2 is independently chosen form a hydrogen, a alkyl group, an ether group, a halogen, or a perfluoroalkyl group; R3 is independently chosen from a hydrogen or an alkyl group, and R4 is independently chosen from a substituted or unsubstituted heteroaromatic group, or a alkanoyl-amine group; or a pharmaceutically acceptable derivative thereof, as an individual stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof FTR. 
       
     
     
         38 . The method of  claim 37 , wherein the gating defective mutant-CFTR is a G551D-CFTR, G1349D-CFTR, or D1152-CFTR. 
     
     
         39 . The method of  claim 37 , wherein said subject is a non-human animal. 
     
     
         40 . The method of  claim 39 , wherein the animal is a mammal.