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, aph thylsulfonyl)-3-(3-guanidinopropyl)-substituted gamma-, delta-, and ep silon-lactams (2-4), were synthesized on the basis of backbone modific ation of the lead structure, 6,7-dimethoxy-2-naphthylsulfonylarginine n-butylmethylamide (1). We tested these compounds for inhibitory activ ity toward thrombin and other trypsin-like enzymes (trypsin, factor Xa , plasmin, and kallikrein). All the compounds synthesized (1-4) potent ly inhibited thrombin with IC50 values of 0.75, 0.70, 0.99, and 3.2 mu M, respectively; they inhibited thrombin over 40-fold more effectivel y than the other enzymes tested. The gamma-lactam (2) with the most pr ofound inhibitory activity toward thrombin was a reversible inhibitor with a K-i of 0.26 mu M. Compound 2 also showed better thrombin select ivity than the lead compound (1), The lactam-conformational restrictio n of arylsulfonylarginine amides, especially gamma-lactam, has thus pr oved to be a useful device for the improvement of antithrombotic activ ity.