| Autor: |
Cheng, M., De, B., Pikul, S., Almstead, N. G., Natchus, M. G., Anastasio, M. V., McPhail, S. J., Snider, C. E., Taiwo, Y. O., Chen, L., Dunaway, C. M., Gu, F., Dowty, M. E., Mieling, G. E., Janusz, M. J., Wang-Weigand, S. |
| Zdroj: |
Journal of Medicinal Chemistry; February 10, 2000, Vol. 43 Issue: 3 p369-380, 12p |
| Abstrakt: |
A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived from dl-piperazinecarboxylic acid has been described. The design involves: incorporation of hydroxamic acid as the bidentate chelating agent for catalytic Zn2+, placement of a sulfonamide group at the 1N-position of the piperazine ring to fill the S1 pocket of the enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and peroral absorption. A unique combination of all three elements produced inhibitor 20 with high affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray crystallography data obtained for MMP-3 cocrystallized with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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