Design of Novel, Potent, Noncovalent Inhibitors of Thrombin with Nonbasic P-1 Substructures: Rapid Structure−Activity Studies by Solid-Phase Synthesis
Journal of Medicinal Chemistry1998Vol. 41(7), pp. 1011–1013
Citations Over TimeTop 10% of 1998 papers
William C. Lumma, Keith M. Witherup, Thomas J. Tucker, Steven F. Brady, John T. Sisko, Adel M. Naylor-Olsen, Sidney D. Lewis, Bobby J. Lucas, Joseph P. Vacca
Abstract
Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.
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