Compounds having activity in correcting mutant-CFTR processing and uses thereof
View Patent ↗The invention provides compositions, pharmaceutical preparations and methods for increasing activity of a mutant cystic fibrosis transmembrane conductance regulator protein (mutant-CFTR). The compositions pharmaceutical preparations and methods are useful for the study and treatment of disorders associated with mutant-CFTR, such as cystic fibrosis. The compositions and pharmaceutical preparations of the invention may comprise one or more bithiazole-containing compounds of the invention, or an analog or derivative thereof.
1. A composition comprising a compound of formula (III):
or the salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof,
wherein:
A and B are aromatic rings each independently selected from thiazole and oxazole, with X 1 , X 2 , X 3 and X 4 being heteroatoms selected from N, O and S, with each dotted line connecting X 1 to X 2 within ring A and X 3 to X 4 within ring B being a single or double bond provided that when one bond is a double bond then the other bond is a single bond;
R 1 is a substituted or unsubstituted group selected from aliphatic and aryl;
R 2 is a substituted or unsubstituted aryl;
R 3 is hydrogen or substituted or unsubstituted aliphatic; and
wherein Z is a bridge comprising a heteroatom or a substituted or unsubstituted lower aliphatic chain.
2. The composition of claim 1 , wherein R 1 is an aliphatic selected from a substituted or unsubstituted alkyl and a substituted or unsubstituted alkenyl.
3. The composition of claim 1 , wherein R 2 is an aryl consisting of a group selected from phenyl and [2,4,6]triazine.
4. The composition of claim 1 , wherein said compound is conjugated to a second molecule.
5. The composition of claim 4 , wherein said second molecule is a mutant-CFTR potentiator compound.
6. The composition of claim 1 , wherein aromatic rings A and B comprise a bithiazole.
7. The composition of claim 1 , wherein the compound is selected from the group consisting of:
or salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof.
8. The composition of claim 1 , wherein Z is selected from methyl, ethyl, propyl, isopropyl, butyl and isobutyl.
9. The composition of claim 1 , wherein the compound is therapeutically effective increasing CFTR-mediated ion permeability of a cell producing a mutant-CFTR, and said composition is a pharmaceutical composition that comprises a therapeutically effective amount of said compound to treat cystic fibrosis.
10. A pharmaceutical composition comprising an effective amount of a mutant-CFTR corrector compound having the formula:
or pharmaceutically acceptable salts, solvates, hydrates, and prodrug forms thereof, and stereoisomers thereof.
11. 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 of claim 9 wherein said condition is cystic fibrosis.
12. A method of increasing ion permeability of a cell producing a mutant-CFTR protein, said method comprising:
contacting said cell with an effective amount of a pharmaceutical composition of claim 9 , said contacting being effective to increase CFTR-mediated ion permeability of said cell to treat cystic fibrosis.
13. The method of claim 12 , wherein the mutant-CFTR is ΔF508-CFTR.
14. A composition comprising a compound of the formula selected from the group consisting of:
wherein R 10 and R 11 are combined to form a ring of six to eight carbons; and
or salt, solvate, hydrate, or prodrug form thereof, or stereoisomers thereof.