Low Molecular Weight, Non-Peptide Fibrinogen Receptor Antagonists

The tetrapeptide H-Arg-Gly-Asp-Ser-OH (1) (RGDS), representing a recognition sequence of fibrinogen for its platelet receptor GP IIb-IIIa (integrin α_IIbβ₃), served as lead compound for the development of highly potent and selective fibrinogen receptor antagonists. Replacement of the N-terminal arginine by p-amidinophenylalanine or the Gly moiety by m-aminobenzoic acid led to compounds which are superior to the lead peptide with regard to activity and selectivity for GP IIb-IIIa vs the closely related vitronectin receptor α_vβ₃. By random screening [(p-amidinobenzenesulfonamido)ethyl]-p-phenoxyacetic acid derivatives have been identified as fibrinogen receptor antagonists. Further structure-activity relationship studies culminated in the preparation of N-[N- [N-(p-amidinobenzoyl)-β-alanyl]-l-α-aspartyl]-3-phenyl-l-alanine (29h,Ro 43-5054) and [[1-[N- (p-amidinobenzoyl)-l-tyrosyl]-4-piperidinyl]oxy] acetic acid (37f, Ro 44-9883), which exhibit very high activity as platelet aggregation inhibitors (IC₅₀s 0.06 and 0.03μM, respectively, human PRP/ADP) as well as marked selectivity for GP IIb-IIIa vs α_vβ₃. Since the activity of 37f in dogs declines according to a two-compartment model with an initial phase having a t_1/2 of 8 min and a second phase with a t_1/2 of 110 min, this compound is a suitable candidate for the development as iv platelet inhibitor.