Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 1. The selection of naphthalene derivatives

The synthesis and design using molecular modeling techniques for non-peptid e, low molecular weight novel fibrinogen receptor (glycoprotein IIb/IIIa: G p IIb/IIIa) antagonists, is reported. We used a highly potent serine protea se inhibitor, Nafamostat, having an amidinonaphthyl unit as the starting co mpound. The compounds 4-(6-amidino-2-naphthylaminocarbonyl)phenoxyacetic ac id (5a) and 4-(6-amidino-2-naphthalenecarboxamido)phenoxyacetic acid (5b) i nhibited adenosin-5'-diphospate (ADP)-induced aggregation of human platelet -rich plasma (PRP) with IC50 values of 0.05 and 0.07 mu M, respectively, an d had lost their ability to inhibit a variety of serine proteases, includin g thrombin, factor Sa, plasmin and trypsin.