| Autor: |
Parlow, J. J., Dice, T. A., Lachance, R. M., Girard, T. J., Stevens, A. M., Stegeman, R. A., Stallings, W. C., Kurumbail, R. G., South, M. S. |
| Zdroj: |
Journal of Medicinal Chemistry; September 2003, Vol. 46 Issue: 19 p4043-4049, 7p |
| Abstrakt: |
A solution-phase synthesis of an α-ketothiazole library of the general form d-Phe-l-AA-Arg-α-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification concepts, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multistep synthesis affords desired α-ketothiazole products in excellent purities and yields. A variety of l-amino acid inputs were used to probe the S2 pocket of tissue Factor VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10k bound to the TF/VIIa complex was obtained that explains the observed selectivity. The α-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue Factor VIIa, with some analogues demonstrating selectivity over thrombin. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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