Design of orally active, non-peptide fibrinogen receptor antagonists. An evolutionary process from the RGD sequence to novel anti-platelet aggregation agents

Abstract The evolutionary process from the Arg-Gly-Asp-Phe (RGDF) tetrapeptide to potent orally active anti-platelet agents is presented. The RGD sequence is an important component in the recognition of fibrinogen by its platelet receptor GP IIb–IIIa (integrin α IIb β 3 ). This work concentrates on the replacement of the Arg-Gly dipeptidyl fragment by an acylated aminobenzamidme. The C-terminal fragment has been replaced by a variety of β-amino acids, expanding on a previously reported paradigm. The lead compounds showed good potency in an in vitro platelet aggregation assay (dog PRP/ADP). The affinity for the fibrinogen receptor was confirmed in several cases by the ability to inhibit 125 I fibrinogen binding to activated human platelets. The ethyl ester prodrug form was tested by oral administration to dogs and monitoring of the anti-platelet effect on ex vivo collagen induced platelet aggregation. From the structural studies reported, the 4-[[(aminoiminomethyl)phenyl]amino]-4-oxo-butanoic acid ( 5 ) was the best surrogate for the Arg-Gly dipeptide. Several conformationally restricted analogues are also reported which are compatible with the hypothesis of RGD binding to the α IIb β 3 in a turn-extended-turn conformation. The structure-activity relationships described also underline the importance of the β-amino acid substitution for potency. In particular, the absolute configuration at the β-carbon was crucial for high affinity. The best acid/ester pairs reported in this study had high potency (acid PRP/ADP IC 50 ⋍ 50 nM) and showed good oral activity in dogs at 5 mg/kg per os (ethyl ester).