Rational design of selective thrombin inhibitors

Abstract

Thrombin inhibitors with functionalized benzamidines as surrogates for arginine were designed, synthesized, and characterized. Amino acid sequence difference in the position 190 between thrombin and trypsin was exploited in the design to enhance selectivity over trypsin. A representative compound 6 showed high potency (Ki of 45.5 nM) and extremely high specificity over trypsin (over 10,000 fold).