Claims
- 1. A method of inhibiting protein kinase activity in a biological sample, wherein said protein kinase is ERK, comprising the step of contacting said sample with a compound comprising Grp1, Grp2, and Grp3, wherein:
Grp 1 is an optionally substituted aryl or aliphatic group; Grp 2 is a heteroaromatic ring comprising one to three nitrogens, and a hydrogen bond acceptor HBA2, wherein HBA2 is optionally bonded to a hydrogen bond donor HBD2; and Grp3 is a heteroaromatic ring comprising a hydrogen bond donor HBD1; wherein
said compound optionally comprises a hydrogen bond acceptor HBA1; and wherein
Grp1 is within about 2.5-10.0 Å of Grp2; Grp2 is within about 4.0-8.0 Å of Grp3; Grp3 is within about 5.0-12.0 Å of Grp1; HBA2 is within about 6.5-11.0 Å of Grp1; HBD1 is within about 6.5-8.5 Å of Grp2; HBD1 is within about 3.5-5.5 Å of HBA1; and HBA1 is within about 6.7-14.0 Å of HBD2.
- 2. The method according to claim 1 wherein the compound comprises hydrogen bond acceptor HBA1.
- 3. The method according to claim 2 wherein the hydrogen bond acceptor HBA2 is bonded to a hydrogen bond donor HBD2.
- 4. The method according to any of claims 1 to 3, wherein:
Grp3 is within about 3.9-8.0 Å of Grp2; Grp2 is within about 5.5-6.6 Å of Grp3; Grp3 is within about 6.0-10.0 Å of Grp1; HBA2 is within about 6.5-11.0 Å of Grp1; HBD1 is within about 7.2-8.2 Å of Grp2; HBD1 is within about 3.9-4.9 Å of HBA1; and HBA1 is within about 7.7-11.7 Å or 11.6-13.6 Å of HBD2.
- 5. The method according to claim 4, wherein:
Grp1 is within about 5.7-6.8 Å of Grp2; Grp2 is within about 5.5-6.6 Å of Grp3; Grp3 is within about 7.2-8.2 Å of Grp1; HBA2 is within about 6.5-11.0 Å of Grp1; HBD1 is within about 7.2-8.2 Å of Grp2; HBD1 is within about 3.9-4.9 Å of HBA1; and HBA1 is within about 10.2-11.2 Å or 12.1-13.1 Å of HBD2.
- 6. The method according to claim 5 wherein Grp2 is a ring selected from Table 1.
- 7. The method according to claim 6 wherein Grp3 is a ring selected from Table 2.
- 8. A composition comprising a compound in an amount sufficient to detectably inhibit protein kinase activity, said protein kinase is ERK; and a pharmaceutically acceptable carrier, wherein said compound comprises Grp1, Grp2 and Grp3, wherein:
Grp 1 is an optionally substituted aryl or aliphatic group; Grp 2 is a heteroaromatic ring comprising one to three nitrogens, and a hydrogen bond acceptor HBA2, wherein HBA2 is optionally bonded to a hydrogen bond donor HBD2; and Grp3 is a heteroaromatic ring comprising a hydrogen bond donor HBD1; wherein
said compound optionally comprises a hydrogen bond acceptor HBA1; and wherein
Grp1 is within about 2.5-10.0 Å of Grp2; Grp2 is within about 4.0-8.0 Å of Grp3; Grp3 is within about 5.0-12.0 Å of Grp1; HBA2 is within about 6.5-11.0 Å of Grp1; HBD1 is within about 6.5-8.5 Å of Grp2; HBD1 is within about 3.5-5.5 Å of HBA1; and HBA1 is within about 6.7-14.0 Å of HBD2.
- 9. The composition according to claim 8 wherein the compound comprises hydrogen bond acceptor HBA1.
- 10. The composition according to claim 9 wherein the hydrogen bond acceptor HBA2 is bonded to a hydrogen bond donor HBD2.
- 11. The composition according to claim 10, wherein:
Grp1 is within about 3.9-8.0 Å of Grp2; Grp2 is within about 5.5-6.6 Å of Grp3; Grp3 is within about 6.0-10.0 Å of Grp1; HBA2 is within about 6.5-11.0 Å of Grp1; HBD1 is within about 7.2-8.2 Å of Grp2; HBD1 is within about 3.9-4.9 Å of HBA1; and HBA1 is within about 7.7-11.7 Å or 11.6-13.6 Å of HBD2.
- 12. The composition according to claim 11, wherein:
Grp1 is within about 5.7-6.8 Å of Grp2; Grp2 is within about 5.5-6.6 Å of Grp3; Grp3 is within about 7.2-8.2 Å of Grp1; HBA2 is within about 6.5-11.0 Å of Grp1; HBD1 is within about 7.2-8.2 Å of Grp2; HBD1 is within about 3.9-4.9 Å of HBA1; and HBA1 is within about 10.2-11.2 Å or 12.1-13.1 Å of HBD2.
- 13. The composition according to claim 12 wherein Grp2 is a ring selected from Table 1.
- 14. The composition according to claim 13 wherein Grp3 is a ring selected from Table 2.
- 15. The composition according to claim 14 wherein said compound is formulated in a pharmaceutically acceptable manner for administration to a patient.
- 16. The composition according to claim 15 further comprising a therapeutic agent, either as part of a multiple dosage form together with said compound or as a separate dosage form.
- 17. A method for treating a disease state in a patient that is alleviated by treatment with a protein kinase inhibitor, wherein said protein kinase is ERK, comprising administering to said patient in need of such a treatment a therapeutically effective amount of a composition according to any of claims 8 to 15.
- 18. The method according to claim 17, comprising the additional step of administering to said patient a therapeutic agent either as part of a multiple dosage form together with said compound or as a separate dosage form.
- 19. The method according to claim 19 wherein said disease state is selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, or CNS disorders.
- 20. A method of treating a disease state in a patient, said disease state selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic reactions, inflammation, neurological disorders or a hormone-related disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a composition according to any of claims 8 to 15.
- 21. The method according to claim 20, comprising the additional step of administering to said patient a therapeutic agent either as part of a multiple dosage form together with said compound or as a separate dosage form.
- 22. The method according to claim 20 wherein the disease state is cancer.
- 23. The method according to claim 20 wherein the disease state is a cardiovascular disease.
- 24. A method of designing an ERK inhibitor, comprising the steps of:
a) selecting a Grp2 moiety containing a hydrogen bond acceptor HBA2, wherein said HBA2 forms a hydrogen bond with the backbone amino hydrogen of Met-108; b) selecting a Grp3 moiety and a means for attachment to Grp2, wherein Grp3 so attached is within the requisite distances to Grp2 and HBA2, and HBD1 forms a hydrogen bond with the sidechain carbonyl of Gln-105; c) selecting a Grp1 moiety and a means for attachment to the fragment formed by steps a) through c); d) selecting a structure type for connecting Grp1, Grp2, and Grp3; e) connecting Grp1, Grp2, and Grp3 according to the structure type selected in step f); f) minimizing the constructed molecule within the protein kinase acitve site; g) optionally selecting an HBA1 group and connecting said HBA1 group to the molecule minimized in step h);
- 25. A composition for coating an implantable device comprising a compound and a carrier suitable for coating said implantable device; wherein said compound comprises Grp1, Grp2 and Grp3, wherein:
Grp 1 is an optionally substituted aryl or aliphatic group; Grp 2 is a heteroaromatic ring comprising one to three nitrogens, and a hydrogen bond acceptor HBA2, wherein HBA2 is optionally bonded to a hydrogen bond donor HBD2; and Grp3 is a heteroaromatic ring comprising a hydrogen bond donor HBD1; wherein
said compound optionally comprises a hydrogen bond acceptor HBA1; and wherein
Grp1 is within about 2.5-10.0 Å of Grp2; Grp2 is within about 4.0-8.0 Å of Grp3; Grp3 is within about 5.0-12.0 Å of Grp1; HBA2 is within about 6.5-11.0 Å of Grp1; HBD1 is within about 6.5-8.5 Å of Grp2; HBD1 is within about 3.5-5.5 Å of HBA1; and HBA1 is within about 6.7-14.0 Å of HBD2.
- 26. An implantable device coated with a composition according to claim 25.
Parent Case Info
[0001] This application claims priority to co-pending International Patent Application PCT/US01/03904, filed Feb. 5, 2001, which claims priority of U.S. Provisional Application serial No. 60/180,502 filed Feb. 5, 2000 and U.S. Provisional Application serial No. 60/191,959 filed Mar. 24, 2000. The entirety of which is herein incorporated by reference.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60180502 |
Feb 2000 |
US |
|
60191959 |
Mar 2000 |
US |