Polymer-Assisted Solution-Phase (PASP) parallel synthesis of an α-ketothiazole library as tissue factor VIIa inhibitors

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

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

A solution-phase synthesis of an α-ketothiazole library of the general form D-Phe-L-AA-L-Arg-α-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification protocols, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multi-step synthesis affords the desired α-ketothiazole products in excellent purities and yields. A variety of L-amino acid inputs were used to probe the S2 pocket of the tissue factor (TF) VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10e 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 versus thrombin.

Original languageEnglish
Pages (from-to)2363-2367
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume13
Issue number14
DOIs
StatePublished - Jul 21 2003

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