| Autor: |
McClure, K. F., Abramov, Y. A., Laird, E. R., Barberia, J. T., Cai, W., Carty, T. J., Cortina, S. R., Danley, D. E., Dipesa, A. J., Donahue, K. M., Dombroski, M. A., Elliott, N. C., Gabel, C. A., Han, S., Hynes, T. R., LeMotte, P. K., Mansour, M. N., Marr, E. S., Letavic, M. A., Pandit, J., Ripin, D. B., Sweeney, F. J., Tan, D., Tao, Y. |
| Zdroj: |
Journal of Medicinal Chemistry; September 2005, Vol. 48 Issue: 18 p5728-5737, 10p |
| Abstrakt: |
Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38α. The computed descriptors for the hydrophobic and π−π interaction capacities were the most useful in ranking potency. |
| Databáze: |
Supplemental Index |
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