Inhibition of VEGF translation
View Patent ↗In accordance with the present invention, methods for inhibiting the translation of VEGF and methods for decreasing VEGF level by inhibiting VEGF translation are provided. In another aspect of the invention, compounds that inhibit the 5′-UTR-dependent translation of VEGF and methods for identifying such compounds are provided.
1. A method for treating a disease associated with elevated levels of VEGF in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (IV):
or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,
X is hydrogen; C 1 to C 6 alkyl optionally substituted with one or more halogens; hydroxyl; halogen; or C 1 to C 5 alkoxy optionally substituted with phenyl;
R o is halogen; cyano; nitro; sulfonyl substituted with C 1 to C 6 alkyl or morpholinyl; amino optionally substituted with C 1 to C 6 alkyl, —C(O)—R b , —C(O)O—R b , alkylsulfonyl, piperidinyl, morpholinyl or tetrahydropyranyl, wherein piperidinyl, morpholinyl or tetrahydropyranyl are optionally further substituted with —C(O)O—R n ; C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from hydroxl, halogen or amino; —C(O)—R n ; —OR a ;
R a is hydrogen; C 2 to C 8 alkenyl; —C(O)O—R b ; —C(O)—NH—R b ; C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, C 1 to C 4 alkoxy, C 1 to C 4 alkoxy-C 1 to C 4 alkoxy, amino, alkylamino, dialkylamino, acetamide, —C(O)—R b , —C(O)O—-R b , aryl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxolan-2-one, oxiranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3-triazole, 1,2,4-triazole, furan, imidazole, isoxazole, isothiazole, oxazole, pyrazole, thiazole, thiophene or tetrazole;
wherein amino is optionally substituted with C 1 to C 4 alkoxycarbonyl, imidazole, isothiazole, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole or thiazole, wherein pyridine and thiazole are each optionally substituted with C 1 to C 4 alkyl;
wherein alkylamino and dialkylamino are each optionally substituted on alkyl with hydroxyl, C 1 to C 4 alkoxy, imidazole, pyrazole, pyrrole or tetrazole; and
wherein morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl and oxiranyl are each optionally substituted with —C(O)—R n , —C(O)O—R n or C 1 to C 4 alkyl, wherein C 1 to C 4 alkyl is optionally substituted with hydroxyl;
R b is hydroxyl; amino; alkylamino, optionally substituted on alkyl with hydroxyl, amino, alkylamino or C 1 to C 4 alkoxy; C 1 to C 4 alkoxy; C 2 to C 8 alkenyl; C 2 to C 8 alkynyl; aryl optionally substituted with one or more substituents independently selected from halogen and C 1 to C 4 alkoxy; furan; or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from C 1 to C 4 alkoxy, aryl, amino, morpholinyl, piperidinyl or piperazinyl, wherein the amino, morpholinyl, piperidinyl and piperazinyl groups are optionally substituted with at least one independently selected C 1 to C 8 alkyl, oxo or —C(O)O—R n substituent;
R d is phenyl optionally substituted by one or more substituents independently selected from halogen, nitro, C 1 to C 6 alkyl, —C(O)O—R e , and —OR e ;
R e is hydrogen; C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halogen and alkoxy; or phenyl, wherein phenyl is optionally substituted with one or more substituents independently selected from halogen and alkoxy; and
R n is hydroxyl, C 1 to C 4 alkoxy, amino or C 1 to C 6 alkyl;
wherein the compound reduces VEGF levels as measured by an ELISA assay or a quantitative immunofluorescence assay, or reduces VEGF levels in HT1080 clones stably expressing epitope-tagged VEGF with a 5′-UTR; and
wherein the disease is solid tumor cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, chronic inflammation, a chronic inflammation-related disease or disorder, obesity, or exudative macular degeneration.
2. The method of claim 1 , wherein
X is C 1 to C 6 alkyl optionally substituted with one or more halogen; halogen; or C 1 to C 5 alkoxy optionally substituted with phenyl;
R o is halogen; cyano; nitro; sulfonyl substituted with C 1 to C 6 alkyl or morpholinyl; amino optionally substituted with C 1 to C 6 alkyl, —C(O)—R b , —C(O)O—R b , alkylsulfonyl, piperidinyl and tetrahydropyranyl, wherein piperidinyl is optionally further substituted with —C(O)O—R n ; C 1 to C 6 alkyl optionally substituted with one or more halogen substituents; —C(O)—R n ; —OR a;
R a is hydrogen; C 2 to C 8 alkenyl; —C(O)O—R b C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, C 1 to C 4 alkoxy, C 1 to C 4 alkoxy-C 1 to C 4 alkoxy, amino, alkylamino, dialkylamino, acetamide, —C(O)—R b , —C(O)O—R b , aryl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxolan-2-one, oxiranyl, 1,2,3-triazole, 1,2,4-triazole, imidazole or pyrazole;
wherein amino is optionally substituted with C 1 to C 4 alkoxycarbonyl, pyridine or thiazole, wherein pyridine and thiazole are each optionally substituted with C 1 to C 4 alkyl;
wherein alkylamino and dialkylamino are each optionally substituted on alkyl with hydroxyl, C 1 to C 4 alkoxy or imidazole; and
wherein morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl and oxiranyl are each optionally substituted with —C(O)—R n , —C(O)O—R n or C 1 to C 4 alkyl, wherein C 1 to C 4 alkyl is optionally substituted with hydroxyl;
R b is hydroxyl; C 1 to C 4 alkoxy; C 2 to C 8 alkenyl; phenyl optionally substituted with one or more halogen substituents; furan; or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from C 1 to C 4 alkoxy, phenyl, amino or morpholinyl, wherein the amino is optionally substituted with at least one independently selected C 1 to C 8 alkyl substituent; and,
R d is phenyl optionally substituted by one or more substituents independently selected from halogen, nitro, C 1 to C 6 alkyl and —OR e ; and,
wherein all other variables are as previously defined.
3. The method of claim 1 , wherein
X is C 1 to C 6 alkyl; halogen; or C 1 to C 5 alkoxy optionally substituted with phenyl;
R o is halogen; cyano; nitro; sulfonyl substituted with C 1 to C 6 alkyl or morpholinyl; amino optionally substituted with —C(O)—R b , —C(O)—R b , alkylsulfonyl, piperidinyl and tetrahydropyranyl, wherein piperidinyl is optionally further substituted with —C(O)O—R n ; C 1 to C 6 alkyl optionally substituted with one or more halogen substituents; —C(O)—R n ; —OR a ;
R a is hydrogen; C 2 to C 8 alkenyl; —C(O)O—R b ; C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, C 1 to C 4 alkoxy, C 1 to C 4 alkoxy-C 1 to C 4 alkoxy, amino, alkylamino, dialkylamino, acetamide, —C(O)O—R b , morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, 1,3-dioxolan-2-one, oxiranyl, 1,2,3-triazole, 1,2,4-triazole, imidazole or pyrazole;
wherein amino is optionally substituted with C 1 to C 4 alkoxycarbonyl, pyridine or thiazole, wherein pyridine and thiazole are each optionally substituted with C 1 to C 4 alkyl;
wherein alkylamino and dialkylamino are each optionally substituted on alkyl with hydroxyl, C 1 to C 4 alkoxy or imidazole; and
wherein morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl and oxiranyl are each optionally substituted with —C(O)O—R n , —C(O)O—R n or C 1 to C 4 alkyl, wherein C 1 to C 4 alkyl is optionally substituted with hydroxyl; and,
R b is hydroxyl; C 1 to C 4 alkoxy; C 2 to C 8 alkenyl; phenyl optionally substituted with one or more halogen substituents; furan; or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from C 1 to C 4 alkoxy or morpholinyl; and
wherein all other variables are as previously defined.
4. The method of claim 1 , wherein the compound is administered orally.
5. The method of claim 1 , wherein the reduction of VEGF levels is measured in an assay using HT1080 clones stably expressing epitope-tagged VEGF with a 5′-UTR.
6. The method of claim 1 , wherein the reduction of elevated VEGF levels is measured by an ELISA assay or a quantitative immunofluorescence assay.
7. The method of claim 1 , wherein said stereoisomer of said compound has a chiral carbon at the point of attachment of the phenyl substituted with R o and said stereoisomer is an (S) isomer at said chiral carbon.
8. A method for treating a disease associated with elevated levels of VEGF in a subject in need thereof comprising administering a therapeutically effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, to the subject; and wherein the disease is solid tumor cancer, diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, chronic inflammation, a chronic inflammation-related disease or disorder, obesity, or exudative macular degeneration.
9. The method of claim 8 , wherein said stereoisomer of said compound has a chiral carbon at the point of attachment of the phenyl ring directly attached to the tricyclic scaffol and said stereoisomer is an (S) isomer at said chiral carbon atom.
10. The method of claim 1 , wherein the disease is solid tumor cancer.
11. The method of claim 10 , wherein the solid tumor cancer is selected from the group consisting of Wilms tumor, neuroblastoma, malignant melanoma, cervical cancer, lung cancer and colon cancer.
12. The method of claim 1 , wherein the disease is diabetic retinopathy.
13. The method of claim 1 , wherein the disease is rheumatoid arthritis.
14. The method of claim 1 , wherein the disease is psoriasis.
15. The method of claim 1 , wherein the disease is atherosclerosis.
16. The method of claim 1 , wherein the disease is chronic inflammation.
17. The method of claim 1 , wherein the disease is a chronic inflammation-related disease or disorder.
18. The method of claim 1 , wherein the disease is obesity.
19. The method of claim 1 , wherein the disease is exudative macular degeneration.
20. The method of claim 10 , wherein said compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 20 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
23. The method of claim 20 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
24. The method of claim 20 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
25. The method of claim 20 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
26. The method of claim 20 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
27. The method of claim 20 , wherein said compound is:
or a pharmaceutically acceptable salt thereof
28. The method of claim 8 , wherein the disease is solid tumor cancer.
29. The method of claim 28 , wherein the solid tumor cancer is selected from the group consisting of Wilms tumor, neuroblastoma, malignant melanoma, cervical cancer, lung cancer and colon cancer.
30. The method of claim 8 , wherein the disease is diabetic retinopathy.
31. The method of claim 8 , wherein the disease is rheumatoid arthritis.
32. The method of claim 8 , wherein the disease is psoriasis.
33. The method of claim 8 , wherein the disease is atherosclerosis.
34. The method of claim 8 , wherein the disease is chronic inflammation.
35. The method of claim 8 , wherein the disease is a chronic inflammation-related disease or disorder.
36. The method of claim 8 , wherein the disease is obesity.
37. The method of claim 8 , wherein the disease is exudative macular degeneration.
38. The method of claim 6 , wherein the reduction of elevated VEGF levels in HeLa cells is measured by an ELISA assay.
39. The method of claim 6 , wherein the reduction of elevated VEGF levels in HT1080 cells is measured by a quantitative immunofluoresence assay.