RATIONAL DESIGN, SYNTHESIS, AND SERINE-PROTEASE INHIBITORY ACTIVITY OF A NOVEL P-1-ARGININAL DERIVATIVE FEATURING A CONFORMATIONALLY CONSTRAINED P-2-P-3-BICYCLIC LACTAM MOIETY

Based on molecular modeling and judicious combination of the salient t opographic features of the recently discovered P-3-lactam derivative 1 with the P-2-prolyl derivatives 2a,b, the novel thrombin inhibitor 3a was designed. Inhibitor 3a incorporates a fused bicyclic lactam as a novel type of P-2-P-3 dipeptide surrogate. The synthesis and biologica l activity of this potent serine protease inhibitor is presented. (C) 1997, Elsevier Science Ltd.