DESIGN, SYNTHESIS, AND IN-VITRO ACTIVITIES OF BENZAMIDE-CORE GLYCOPROTEIN IIB IIIA ANTAGONISTS - 2,3-DIAMINOPROPIONIC ACID-DERIVATIVES AS SURROGATES OF ASPARTIC-ACID/

In an effort to discover novel nonpeptide glycoprotein IIb/IIIa (GPIIb /lIIa, alpha(IIb)/beta 3) inhibitors, we investigated RGD mimetics fea turing a 3-substituted benzoic acid as the core, benzamidine as the ba sic moiety, and a series of beta- and alpha-substituted beta-alanine d erivatives as aspartic acid surrogates. It was found that the use of b eta-methyl beta-alanine slightly improved the anti-aggregant potency i n human platelet-rich plasma over the unsubstituted beta-alanine compo und, while alpha-substitution with a trifluoromethyl group resulted in considerable loss in activity. Significant enhancement (up to 100-fol d) in potency was obtained when the beta-alanine was replaced with N-2 -substituted L-2,3-diaminopropionic acid derivatives. Among the three types of cc-substituents (carbamate, amide, and sulfonamide) investiga ted, no apparent preference was observed with respect to in vitro pote ncy. However, alkyl groups were more favorable than arylalkyl groups ( Cbz) in the carbamate analogues. We also investigated piperidine, pipe razine, and N-formamidinopiperidine as replacements for the benzamidin e moiety. The former two replacements led to a drop in potency while t he latter replacement resulted in maintenance of activity as compared with the corresponding benzamidine analogue. (C) 1997 The DuPont Merck Pharmaceutical Company. Published by Elsevier Science Ltd.