Lactam-Conformationally Restricted Analogs of N.ALPHA.-Arylsulfonyl Arginine Amide: Design, Synthesis and Inhibitory Activity toward Thrombin and Related Enzymes.

Three new lactam-conformationally restricted arginine derivatives, 1-butyl-3-(6, 7-dimethoxy-2-naphthylsulfonyl)-3-(3-guanidinoropyl)-substituted γ-, δ-, and e-lactams (2-4), were synthesized on the basis of backbone modification of the lead structure, 6, 7-dimethoxy-2-naphthylsulfonylarginine n-butylmethylamide (1). We tested these compounds for inhibitory activity toward thrombin and other trypsin-like enzymes (trypsin, factor Xa, plasmin, and kallikrein). All the compounds synthesized (1-4) potently inhibited thrombin with IC50 values of 0.75, 0.70, 0.92, and 3.2μM, respectively; they inhibited thrombin over 40-fold more effectively than the other enzymes tested. The γ-lactam (2) with the most profound inhibitory activity toward thrombin was a reversible inhibitor with a Ki of 0.26μM. Compound 2 also showed better thrombin selectivity than the lead compound (1). The lactam-conformational restriction of arylsulfonylarginine amides, especially γ-lactam, has thus proved to be a useful device for the improvement of antithrombotic activity.