Design of Novel, Potent, Noncovalent Inhibitors of Thrombin with Nonbasic P-1 Substructures: Rapid Structure−Activity Studies by Solid-Phase Synthesis
- 1 March 1998
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 41 (7) , 1011-1013
- https://doi.org/10.1021/jm9706933
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.Keywords
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