Use of Conformationally Restricted Benzamidines as Arginine Surrogates in the Design of Platelet GPIIb-IIIa Receptor Antagonists

The use of 5,6-bicyclic amidines as arginine surrogates in the design of a novel class of potent platelet glycoprotein IIb-IIIa receptor (GPIIb-IIIa) antagonists is described. The additional conformational restriction offered by the bicyclic nucleus results in 20−400-fold increases in potency compared to the freely flexible, acyclic benzamidine counterpart. The design, synthesis, structure−activity relationships (SAR), and in vitro activity of this novel class of GPIIb-IIIa antagonists are presented.