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

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 IIbβ 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 The C-terminal fragment has been replaced by a variety of β-amino acids, expanding on a previously reported paradigm.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 125I 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 IIbβ 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). The design of potent, non-peptide fibrinogen receptor antagonists based on the Arg-Gly-Asp (RGD) sequence is presented. An ethyl ester prodrug of several compounds, e.g., where R = (S)-3-pyridyl, were orally active in the dog; in vivo activity was measured with an ex vivo antiaggregatory assay.