Coumarin derivatives and methods of use in treating cystic fibrosis, chronic obstructive pulmonary disease, and misfolded protein disorders
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 and chronic obstructive pulmonary diseases). 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 or prodrug thereof, wherein:
R 1 is hydrogen, halogen, hydroxyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted amino, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted heterocycloalkyl;
R 2 is halogen, hydroxyl, nitro, cyano, azido, thiocyanato, trifluoromethyl, substituted or unsubstituted amino, substituted or unsubstituted carbonyl, or substituted or unsubstituted C 1-6 alkyl;
R 3 is hydrogen or substituted or unsubstituted C 1-6 alkyl;
R 4 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
X is S or O; and
Y is O, NH, or NCH 3 .
2. The compound of claim 1 , wherein the compound is selected from the group consisting of:
wherein R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted alkoxy, cyano, nitro, trifluoromethyl, substituted or unsubstituted carbonyl, substituted or unsubstituted amino, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted sulfonamide, substituted or unsubstituted sulfonyl, or substituted or unsubstituted thio; and
wherein optionally R 1 and R 2 , R 5 and R 6 , R 6 and R 7 , R 7 and R 8 , or R 8 and R 9 combine to form a substituted or unsubstituted aryl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.
3. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
L is a heteroaryl; and
R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen and methoxy.
4. A composition comprising one or more of the compounds of claim 1 and a pharmaceutically acceptable carrier.
5. A method for the treatment of a protein folding disorder in a subject, comprising:
administering to a subject an effective amount of a compound of claim 1 .
6. The method of claim 5 , wherein the protein folding disorder is cystic fibrosis.
7. The method of claim 5 , wherein the protein folding disorder is a chronic obstructive pulmonary disease.
8. 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.
9. The method of claim 8 , wherein the CFTR mutation is delF508-CFTR.
10. The method of claim 8 , wherein the halide efflux is chloride efflux.
11. 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.
12. The method of claim 8 , wherein the cell is a CF human airway epithelial cell.
13. The method of claim 8 , wherein the cell is a CF human lung.
14. 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.
15. The method of claim 8 , wherein the method is performed in vitro.
16. The method of claim 8 , wherein the method is performed in vivo.
17. The compound of claim 1 , wherein the compound is
18. The compound of claim 1 , wherein R 1 is hydrogen, R 2 is trifluoromethyl, R 4 is substituted aryl, X is S, and Y is O.
19. The compound of claim 2 , wherein the compound is
and
wherein R 1 is hydrogen, R 2 is trifluoromethyl, R 5 is substituted or unsubstituted alkoxy, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, and R 9 is hydrogen.
20. A compound of the following formula:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X 1 , X 2 , X 3 and X 4 are each CH;
Y is O or NR, where R is hydrogen or methyl;
R 2 is C 1-6 alkyl, halogen, or trifluoroalkyl; and
R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen and methoxy.
21. A compound of the following formula:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 and R 2 are each independently selected from hydrogen, substituted or unsubstituted amino, and substituted or unsubstituted carbonyl,
wherein at least one of R 1 or R 2 is substituted amino.
22. A compound of the following formula:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X is CH 2 , NH, or O.