DESIGN AND EVALUATION OF NONPEPTIDE FIBRINOGEN GAMMA-CHAIN BASED GPIIB IIIA ANTAGONISTS/

Two series of nonpeptide turn mimetics were designed by analysis of th e solution NMR structure of the 385-411 sequence of the gamma-chain of fibrinogen. These compounds, based on the KQAGD (Lys-Gln-Ala-Gly-Asp, 406-410) sequence, were synthesized and studied in vitro. The most in teresting compound from our study, RWJ 50042 (25), exhibits potent inh ibition of fibrinogen binding to GPIIb/IIIa (IC50 = 0.009 mu M), as we ll as thrombin- or collagen-induced platelet aggregation (IC50 = 0.76, 0.14 mu M). Since the 400-411 sequence is required for gamma-chain bi oactivity and is a unique recognition sequence among ligands for integ rins, vis-a-vis other RGD (Arg-Gly-Asp)-presenting proteins, these tur n mimetics may represent a new, selective approach to antagonism of th e fibrinogen receptor.