Design of a potent and orally active nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist

The direct design of the potent nonpeptide platelet fibrinogen receptor (GPIIb/IIIa) antagonist, 8-[[[4-(aminoiminomethyl)phenyl]amino]carbonyl]-2,3,4, ( 3) (SB 207448), based on the structure and conformation of the potent and highly constrained cyclic peptide antagonist SK&F 107260 ( 2), has been reported [Ku et al., J. Am. Chem. Soc. 1993, 115, 8861]. While 3 displayed in vivo activity in the conscious dog following intravenous administration, it was not active following intraduodenal administration; activity was measured with an ex vivo platelet aggregation assay. The secondary amide in 3 was N-methylated in the expectation of increased absorption and bioavailability. The resulting tertiary amide, 4 (SB 208651), also showed high binding affinity for human GPIIb/IIIa and potent antiaggregatory activity in human platelet-rich plasma. Most importantly, 4 was active in vivo following intravenous and intraduodenal administration. Comparison of the iv and id inhibition curves suggests an apparent bioavailability of approximately 10 %. Thus, 4 represents the first orally active compound in this series of potent, nonpeptide fibrinogen receptor antagonists. N-Methylation of the potent, nonpeptide GPIIb/IIIa antagonist 3 (SB 207448) gave 4 (SB 208651); both compounds have high affinity for human GPIIb/IIIa and are potent inhibitors of human platelet aggregation in vitro, however, only 4 displayed oral activity following intraduodenal administration.