Novel Non-Peptide GPIIb/IIIa Antagonists : Synthesis and Biological Activities of 2-[4-[2-(4-Amidinobenzoylamino)-2-(substituted)acetyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyl]acetic Acids

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To improve the in vitro and in vivo potency of our first low molecular weight GPIIb/IIIa antagonist 1(TAK-029), a series of 2-[4-[2-(4-amidinobenzoylamino)-2-(substituted)acetyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyl]acetic acids were synthesized through modification of the glycine moiety of 1 and evaluated for their ability to inhibit in vitro adenosine 5'-diphosphate(ADP)-induced platelet aggregation of guinea pig platele rich plasma(PRP). Among the compounds examined, the(3S, 2S)-4-methoxyphenylalanine derivative 4h showed the most potent antagonistic activity with an IC_<50> value of 13n_M. Dose-dependent inhibition of ex vivo platelet aggregation was achieved with oral administration of 4h(0.3-1.0mg/kg)to guinea pigs. Complete inhibition was observed for up to 8h, and 43% inhibition could still be observed 24h after oral administration of 1.0mg/kg. The long-lasting antiplatelet effect of 4h suggests that 4h would be suitable for once-a-day dosing. Structure-activity relationships(SAR)were examined in the series of the phenylalanine derivatives. An increase in the electon density around the 4-position of the phenyl ring of the phenylalanine moiety led to an increase in the antiplatelet activity, suggesting the existence of a hydrophobic and electrostatic interaction site in addition to the ionic binding sites in the GPIIb/IIIa.
社団法人日本薬学会の論文
2001-03-01