DESIGN OF BENZAMIDINE-TYPE INHIBITORS OF FACTOR XA

A series of derivatives of rac-benzenesulfonyl-glycyl-phenylalanine or its ethyl ester with a combination of thioamido/amidino or amidino/am idino substituents in the benzene rings was synthesized as potential i nhibitors of factor Xa (Ma). Among these, the racemic idinobenzenesulf onyl-glycyl-4-amidinophenylalanine ethyl ester was found to exhibit th e highest affinity for fXa despite the unfavored location of the amidi no substituent in the para position. X-ray structural analysis of the trypsin complex with this bis-benzamidine compound revealed a retro-bi nding mode if compared to those of similar compounds, so far analyzed in complexes with trypsin or fXa. This noncanonical binding mode as we ll as its slow plasma clearance rates in rats, if compared to those of other benzamidine derivatives, suggests this compound as an interesti ng new lead structure for the design of fXa inhibitors.