DESIGN OF NOVEL, POTENT, NONCOVALENT INHIBITORS OF THROMBIN WITH NONBASIC P-1 SUBSTRUCTURES - RAPID STRUCTURE-ACTIVITY STUDIES BY SOLID-PHASE SYNTHESIS

Study of surface representations of the inhibitor-bound thrombin P-1 p ocket revealed a lipophilic recess in this pocket which is not occupie d by any known inhibitor. Solid-phase synthesis was used to generate b enzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-1 3 000 nM, and the structure-activity relationships and molecular model ing suggest a unique fit of the benzyl side chain into P-1 with the me ta substituent occupying the recess.