LACTAM-CONFORMATIONALLY RESTRICTED ANALOGS OF N-ALPHA-ARYLSULFONYL ARGININE AMIDE - DESIGN, SYNTHESIS AND INHIBITORY ACTIVITY TOWARD THROMBIN AND RELATED ENZYMES
T. Okayama et al., LACTAM-CONFORMATIONALLY RESTRICTED ANALOGS OF N-ALPHA-ARYLSULFONYL ARGININE AMIDE - DESIGN, SYNTHESIS AND INHIBITORY ACTIVITY TOWARD THROMBIN AND RELATED ENZYMES, Chemical and Pharmaceutical Bulletin, 43(10), 1995, pp. 1683-1691
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.