CONFORMATIONALLY CONSTRAINED PEPTIDES AND SEMIPEPTIDES DERIVED FROM RGD AS POTENT INHIBITORS OF THE PLATELET FIBRINOGEN RECEPTOR AND PLATELET-AGGREGATION

Structure-activity studies have been pursued on cyclo-S,S-[Ac-Cys-(Na- Me)Arg-Gly-Asp-Pen[-NH2, 2 (SK&F 106760), a potent inhibitor of platel et aggregation, in an effort to improve potency and affinity for the G PIIb/IIIa receptor. Modifications on the N- and C-termini of 2 produce d a series of peptides which indicate that the C-terminal carboxylate group may be a secondary receptor-binding element. Further modificatio n by replacing the disulfide tether N(alpha)-etylcysteine/penicillamin eamide with the novel, inexpensive, achiral, constrained, and more lip ophilic tether 2-mercaptobenzoyl/2-mercaptoaniline (Mba/Man) afforded the semipeptide cyclo-S,S-[Mba-(N(alpha)-ME)Arg-Gly-Asp-Man], 18&F 107 260), which exhibited significant enhancement in both affinity and pot ency. To further investigate the effect of the phenyl ring at the C-te rminus, peptides bearing the novel (2R,3S)- and (2R,3R)-beta-phenylcys teines were synthesized, which culminated in the N(alpha)-Me)Arg-Gly-A sp-(2R,3S)-beta-phenylCys]-OH peptide, 22, which displayed substantial affinity and potency. We describe, herein, the development of both 18 and 22 and the additional structural modifications within the constra ined cyclic disulfide ring to probe the stereochemical and steric requ irements for receptor interaction.