Lactam-Cohformationally Restricted Analogs of N^α-Arylsulfonyl Arginine Amide : Design, Synthesis and Inhibitory Activity toward Thrombin and Related Enzymes

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Three new lactam-conformationally restricted arginine derivatives, 1-butyl-3-(6,7-dimethoxy-2-naphthylsulfonyl)-3-(3-guanidinoropyl)-substituted γ-, δ-, and ε-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 IC_<50> 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 K_i 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.
公益社団法人日本薬学会の論文
1995-10-15