Rational design, synthesis, and serine protease inhibitory activity of a novel P1-argininal derivative featuring a conformationally constrained P2–P3 bicyclic lactam moiety

Based on molecular modeling and judicious combination of the salient topographic features of the recently discovered P3-lactam derivative 1 with the P2-prolyl derivatives 2a, b, the novel thrombin inhibitor 3a was designed. Inhibitor 3a incorporates a fused bicyclic lactam as a novel type of P2–P3 dipeptide surrogate. The synthesis and biological activity of this potent serine protease inhibitor is presented.