Small molecule CFTR correctors
Novel CFTR corrector compounds that are effective in rescuing halide efflux, delF508-CFTR protein processing, and apical functional chloride ion transport in a cell are provided. Also provided are methods for treating protein folding disorders (e.g., cystic fibrosis). The methods include administering a CFTR corrector compound or pharmaceutically acceptable salt or prodrug thereof. Methods of rescuing halide efflux in a cell, correcting a processing defect of a delF508-CFTR protein in a cell, and correcting functional delF508-CFTR chloride channels in a cell are also provided.
1. A compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is substituted aryl;
R 2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; and
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, or substituted carbonyl,
wherein when R 2 is hydrogen and R 3 is methyl, then R 1 is not p-chlorophenyl.
2. A compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is substituted aryl;
R 2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl;
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, or substituted carbonyl; and
R 10 and R 11 are each independently selected from the group consisting of hydrogen and substituted or unsubstituted alkyl.
3. A compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is substituted aryl;
R 2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl;
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, or substituted carbonyl; and
R 12 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl,
wherein when R 2 is hydrogen and R 3 is methyl, then R 1 is not p-chlorophenyl.
4. A compound selected from the group consisting of:
5. A compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen and substituted or unsubstituted alkyl; and
R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl.
6. The compound of claim 5 , wherein the compound is
7. A compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
X is O or NR 1 , wherein R 1 is hydrogen or substituted or unsubstituted alkyl;
R 2 is hydrogen;
R 3 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; and
R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl.
8. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
9. A method for the treatment of a protein folding disorder in a subject, comprising:
administering to the subject an effective amount of a compound of claim 1 .
10. The method of claim 9 , wherein the protein folding disorder is cystic fibrosis.
11. A method of rescuing halide efflux in a cell, comprising:
contacting a cell with a compound of claim 1 , wherein the cell endogenously expresses a CFTR mutation.
12. The method of claim 11 , wherein the CFTR mutation is delF508-CFTR.
13. The method of claim 11 , wherein the halide efflux is chloride efflux.
14. A method of correcting a processing defect of a delF508-CFTR protein in a cell, comprising:
contacting a cell with a compound of claim 1 , wherein the cell expresses a delF508-CFTR mutation.
15. The method of claim 11 , wherein the cell is a CF human airway epithelial cell.
16. The method of claim 11 , wherein the cell is a CF human lung.
17. A method of correcting functional delF508-CFTR chloride channels in a cell, comprising:
contacting a cell with a compound of claim 1 , wherein the cell is a polarized epithelial cell.
18. The method of claim 11 , wherein the method is performed in vitro.
19. The method of claim 11 , wherein the method is performed in vivo.
20. The compound of claim 1 , wherein the compound has the following structure: