Polymer-assisted solution-phase library synthesis and crystal structure of α-ketothiazoles as tissue factor VIIa inhibitors

John J. Parlow, Thomas A. Dice, Rhonda M. Lachance, Thomas J. Girard, Anna M. Stevens, Roderick A. Stegeman, William C. Stallings, Ravi G. Kurumbail, Michael S. South

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31 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4043-4049
Number of pages7
JournalJournal of Medicinal Chemistry
Volume46
Issue number19
DOIs
StatePublished - Sep 11 2003
Externally publishedYes

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    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. (2003). Polymer-assisted solution-phase library synthesis and crystal structure of α-ketothiazoles as tissue factor VIIa inhibitors. Journal of Medicinal Chemistry, 46(19), 4043-4049. https://doi.org/10.1021/jm030130t