Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: rapid structure-activity studies by solid-phase synthesis

Journal of Medicinal Chemistry
W C LummaJ 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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Citations

Apr 3, 1999·Medicinal Research Reviews·P E Sanderson
Sep 25, 2004·Medicinal Research Reviews·Stuti SrivastavaDinesh K Dikshit
Mar 13, 1999·Thrombosis Research·J Hauptmann, J Stürzebecher
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Nov 1, 2002·Journal of Medicinal Chemistry·Cristiano Ruch Werneck Guimarães, Ricardo Bicca de Alencastro

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