piperidines and 2-3-diaminopropionic-acid

In an effort to discover novel nonpeptide glycoprotein IIb/IIIa (GPIIb/IIIa, alpha IIb/beta 3) inhibitors, we investigated RGD mimetics featuring a 3-substituted benzoic acid as the core, benzamidine as the basic moiety, and a series of beta- and alpha-substituted beta-alanine derivatives as aspartic acid surrogates. It was found that the use of beta-methyl beta-alanine slightly improved the anti-aggregant potency in human platelet-rich plasma over the unsubstituted beta-alanine compound, while beta-substitution with a trifluoromethyl group resulted in considerable loss in activity. Significant enhancement (up to 100-fold) in potency was obtained when the beta-alanine was replaced with N2-substituted 1-2,3-diaminopropionic acid derivatives. Among the three types of alpha-substituents (carbamate, amide, and sulfonamide) investigated, no apparent preference was observed with respect to in vitro potency. However, alkyl groups were more favorable than arylalkyl groups (Cbz) in the carbamate analogues. We also investigated piperidine, piperazine, and N-formamidinopiperidine as replacements for the benzamidine moiety. The former two replacements led to a drop in potency while the latter replacement resulted in maintenance of activity as compared with the corresponding benzamidine analogue.

Topics: Alanine; Alkylation; Animals; Aspartic Acid; Benzamides; Benzamidines; Benzoates; Benzoic Acid; beta-Alanine; Carbamates; Esterases; Humans; Liver; Magnetic Resonance Spectroscopy; Oligopeptides; Piperazine; Piperazines; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Structure-Activity Relationship; Sulfonamides; Swine