US2015065539A1PendingUtilityA1

Methods for Increasing CFTR Activity

45
Assignee: UAB RESEARCH FOUNDATIONPriority: Apr 6, 2012Filed: Mar 15, 2013Published: Mar 5, 2015
Est. expiryApr 6, 2032(~5.7 yrs left)· nominal 20-yr term from priority
Inventors:Steven RoweMark Dransfield
A61P 37/02A61P 31/00A61P 29/00A61K 31/47A61P 11/00A61P 11/06A61P 21/00A61P 25/00
45
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Claims

Abstract

The present disclosure provides compounds effective in increasing mucociliary clearance in a subject. In one embodiment, the compounds are of the general formula I. The present disclosure further shows that such compounds are effective in increasing activation of the CFTR, thereby increasing mucociliary clearance in the subject. The present disclosure further shows that such compounds are effective in increasing the depth of ASL, thereby increasing mucociliary clearance in the subject. In one embodiment of each of the foregoing, the subject is free from congenital or genetic defect in the cellular mucociliary clearance apparatus and/or acquired abnormality in the cellular mucociliary clearance apparatus.

Claims

exact text as granted — not AI-modified
What is claimed: 
     
         1 . A method for increasing mucociliary clearance in a subject the method comprising the step of administering to the subject an activator of the cystic fibrosis transmembrane conductance regulator (CFTR), wherein the subject is free from congenital or genetic defect in the cellular mucociliary clearance apparatus. 
     
     
         2 . The method of  claim 1 , wherein the subject is free from congenital or genetic defect in the CFTR. 
     
     
         3 . The method of  claim 1 , wherein the subject is free an acquired abnormality in the cellular mucociliary clearance apparatus. 
     
     
         4 . The method of  claim 1 , wherein the subject is free an acquired abnormality in the CFTR. 
     
     
         5 . The method of  claim 1 , wherein the subject is free from congenital or genetic defect in the cellular mucociliary clearance apparatus and an acquired abnormality in the cellular mucociliary clearance apparatus. 
     
     
         6 . The method of  claim 1 , wherein the activator of the CFTR is a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is ═O, OH or H; and 
         R 2  and R 3  are each independently, H, OH or substituted or unsubstituted C1-C7 alkyl. 
       
     
     
         7 . The method of  claim 1 , wherein the activator of the CFTR is a compound of the formula 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein said treatment increases a parameter of airway epithelial cell function. 
     
     
         9 . The method of  claim 8 , wherein such parameter is depth of (ASL), depth of periciliary liquid (PCL), ciliary beat frequency (CBF), rate of mucociliary transport (MCT) or any combination of the foregoing. 
     
     
         10 . The method of  claim 8 , wherein such parameter is depth of ASL, rate of MCT or a combination of the foregoing. 
     
     
         11 . The method of  claim 10 , wherein the subject is free from congenital or genetic defect in the CFTR 
     
     
         12 . The method of  claim 10 , wherein the subject is free an acquired abnormality in the cellular mucociliary clearance apparatus. 
     
     
         13 . The method of  claim 1 , wherein said administering increases the activity of the CFTR. 
     
     
         14 . A method for treating suboptimal mucociliary clearance in a subject the method comprising the step of administering to the subject an activator of the cystic fibrosis transmembrane conductance regulator (CFTR), wherein the subject is free from congenital or genetic defect in the cellular mucociliary clearance apparatus. 
     
     
         15 . The method of  claim 14 , wherein the subject is free from congenital or genetic defect in the CFTR. 
     
     
         16 . The method of  claim 14 , wherein the subject is free an acquired abnormality in the cellular mucociliary clearance apparatus. 
     
     
         17 . The method of  claim 14 , wherein the subject is free an acquired abnormality in the CFTR. 
     
     
         18 . The method of  claim 14 , wherein the subject is free from congenital or genetic defect in the cellular mucociliary clearance apparatus and an acquired abnormality in the cellular mucociliary clearance apparatus. 
     
     
         19 . The method of  claim 14 , wherein the activator of the CFTR is a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is ═O, OH or H; and 
         R 2  and R 3  are each independently, H, OH or substituted or unsubstituted C1-C7 alkyl. 
       
     
     
         20 . The method of  claim 14 , wherein the activator of the CFTR is a compound of the formula 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 14 , wherein said treatment increases a parameter of airway epithelial cell function. 
     
     
         22 . The method of  claim 21 , wherein such parameter is depth of (ASL), depth of periciliary liquid (PCL), ciliary beat frequency (CBF), rate of mucociliary transport (MCT) or any combination of the foregoing. 
     
     
         23 . The method of  claim 21 , wherein such parameter is depth of ASL, rate of MCT or a combination of the foregoing. 
     
     
         24 . The method of  claim 23 , wherein the subject is free from congenital or genetic defect in the CFTR 
     
     
         25 . The method of  claim 23 , wherein the subject is free an acquired abnormality in the cellular mucociliary clearance apparatus. 
     
     
         26 . The method of  claim 14 , wherein said treatment increases the activity of the CFTR. 
     
     
         27 . A method for enhancing a parameter of airway epithelial cell function in a subject the method comprising the step of administering to the subject an activator of the cystic fibrosis transmembrane conductance regulator (CFTR), wherein the subject is free from congenital or genetic defect in the cellular mucociliary clearance apparatus. 
     
     
         28 . The method of  claim 27 , wherein the subject is free from congenital or genetic defect in the CFTR. 
     
     
         29 . The method of  claim 27 , wherein the subject is free an acquired abnormality in the cellular mucociliary clearance apparatus. 
     
     
         30 . The method of  claim 27 , wherein the subject is free an acquired abnormality in the CFTR. 
     
     
         31 . The method of  claim 27 , wherein the subject is free from congenital or genetic defect in the cellular mucociliary clearance apparatus and an acquired abnormality in the cellular mucociliary clearance apparatus. 
     
     
         32 . The method of  claim 27 , wherein the activator of the CFTR is a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is ═O, OH or H; and 
         R 2  and R 3  are each independently, H, OH or substituted or unsubstituted C1-C7 alkyl. 
       
     
     
         33 . The method of  claim 27 , wherein the activator of the CFTR is a compound of the formula 
       
         
           
           
               
               
           
         
       
     
     
         34 . The method of  claim 27 , wherein such parameter is depth of airway surface liquid (ASL), depth of periciliary liquid (PCL), ciliary beat frequency (CBF), rate of mucociliary transport (MCT) or any combination of the foregoing. 
     
     
         35 . The method of  claim 27 , wherein such parameter is depth of ASL rate of MCT or a combination of the foregoing. 
     
     
         36 . The method of  claim 27 , wherein said administering increases the rate of MCT. 
     
     
         37 . The method of  claim 27 , wherein said administering increases the depth of ASL. 
     
     
         38 . The method of  claim 27 , wherein said administering increases the depth of PCL. 
     
     
         39 . The method of  claim 27 , wherein said administering increases CBF. 
     
     
         40 . The method of  claim 35 , wherein the subject is free from congenital or genetic defect in the CFTR 
     
     
         41 . The method of  claim 35 , wherein the subject is free an acquired abnormality in the cellular mucociliary clearance apparatus. 
     
     
         42 . The method of  claim 27 , wherein said administering increases the activity of the CFTR.

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