Analogs of the natural product icariin
View Patent ↗Provided herein are analogs of the natural product icariin represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. The analogs can be used to modulate (e.g., inhibit, such as by competitive inhibition) PDE5 and thereby treat a wide range of PDE5-mediated diseases, including cardiovascular, gastrointestinal, pulmonary, musculoskeletal, neurological and reproductive diseases. Also provided herein are compositions and methods including compounds of Structural Formula (I).
1. A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —O-monosaccharide, hydroxy, hydrogen, halogen or carboxy, or —C(O)O(C 1 -C 10 )alkyl, —C(O)O(C 1 -C 10 )alkenyl or —C(O)O(C 1 -C 10 )alkynyl optionally substituted with one or more substituents independently selected from (C 1 -C 5 )alkylamino, (C 1 -C 5 )alkoxy, amino, cyano, (C 1 -C 5 )dialkylamino, halo(C 1 -C 5 )alkoxy, halogen, hydroxy, nitro, thio or thio(C 1 -C 5 )alkoxy;
R 2 is hydroxy, —O-monosaccharide, hydrogen, halogen or (C 1 -C 10 )alkoxy optionally substituted with one or more substituents independently selected from (C 1 -C 5 )alkylamino, (C 1 -C 5 )alkoxy, amino, cyano, (C 1 -C 5 )dialkylamino, halo(C 1 -C 5 )alkoxy, halogen, hydroxy, nitro, thio or thio(C 1 -C 5 )alkoxy;
R 3 is hydroxy(C 1 -C 5 )alkyl;
Ring A is a (C 3 -C 15 )unsaturated or aromatic carbocyclyl or a (C 3 -C 15 )unsaturated or aromatic heterocyclyl;
each R 4 is independently (C 1 -C 10 )alkyl, (C 1 -C 10 )alkylamino, (C 1 -C 10 )alkenyl, (C 1 -C 10 )alkenoxy, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkynyl, (C 1 -C 10 )acyl, (C 1 -C 10 )alkanoyl, amido, amino, formyl, (C 6 -C 15 )aryl, (C 6 -C 15 )aryloxy, carboxy, cyano, (C 3 -C 15 )cycloalkyl, (C 3 -C 15 )cycloalkoxy, (C 1 -C 10 )dialkylamino, (C 1 -C 10 )ether, halo(C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkoxy, halogen, (C 5 -C 13 )heteroaryl, (C 5 -C 15 )heteroaryloxy, (C 3 -C 15 )heterocyclyl, (C 3 -C 15 )heterocyclyloxy, hydroxy, nitro, phosphate, phosphonate, sulfate, sulfonyl, sulfonamide, sulfonate, thio or thio(C 1 -C 10 )alkoxy; and
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14.
2. The compound of claim 1 , wherein R 1 is —O-monosaccharide or hydroxy.
3. The compound of claim 2 , wherein R 1 is —O-monosaccharide.
4. The compound of claim 3 , wherein R 1 is a hexose.
5. The compound of claim 4 , wherein R 1 is selected from allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, fucose or rhamnose.
6. The compound of claim 5 , wherein R 1 is glucose.
7. The compound of claim 2 , wherein R 1 is hydroxy.
8. The compound of claim 1 , wherein R 2 is hydroxy.
9. The compound of claim 1 , wherein R 3 is hydroxyethyl or hydroxypropyl.
10. The compound of claim 1 , wherein R 3 is 2-hydroxyethyl, 3-hydroxypropyl or 2-hydroxypropyl.
11. The compound of claim 1 , wherein Ring A is a (C 6 -C 15 )aryl or a (C 5 -C 15 )heteroaryl.
12. The compound of claim 11 , wherein Ring A is a C 5 heteroaryl and n is 0, 1, 2, 3 or 4; or Ring A is a C 6 heteroaryl and n is 0, 1, 2, 3, 4 or 5.
13. The compound of claim 1 , represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, 4 or 5.
14. The compound of claim 13 , represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein n is 1.
16. The compound of claim 1 , wherein each monosaccharide is independently selected from a pentose and a hexose.
17. The compound of claim 16 , wherein each pentose is independently selected from arabinose, lyxose, ribose, xylose, ribulose, xylulose, deoxyribose or fuculose.
18. The compound of claim 16 , wherein each hexose is independently selected from allose, altrose, glucose, mannose, gulose, idose, galactose, talose, psicose, fructose, sorbose, tagatose, fucose or rhamnose.
19. A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
20. A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
21. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
22. A method of treating a cardiovascular, gastrointestinal, pulmonary, musculoskeletal, neurological or reproductive disease, disorder or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
23. A method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
24. A method of treating an inflammatory or autoimmune disease, disorder or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.