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Potent Dibasic GPIIb/IIIa Antagonists with Reduced Prolongation of Bleeding Time: Synthesis and Pharmacological Evaluation of 2-Oxopiperazine Derivatives

2001; American Chemical Society; Volume: 44; Issue: 15 Linguagem: Inglês

10.1021/jm0004345

1520-4804

Shuji Kitamura, Hideto Fukushi, Toshio Miyawaki, Masaki Kawamura, Noriko Konishi, Zen‐ichi Terashita, Takehiko Naka,

Antiplatelet Therapy and Cardiovascular Diseases

A series of 2-oxopiperazine derivatives, possessing basic moieties at the 3- and the 4-positions, were synthesized and evaluated for their abilities to inhibit platelet aggregation and for their effects on bleeding time. Among the compounds, 2-[(3S)-4-[2-[(4-guanidinobenzoyl)amino]acetyl]-3-[3-[(4-guanidinobenzoyl)amino]propyl]-2-oxopiperazinyl]acetic acid (12c) showed a potent inhibitory effect on platelet aggregation and good dissociation between the efficacy and the bleeding side effect. Intravenous infusion of compound 12c at 1.6 microg/mL/min completely prevented arterial thrombus formation induced by endothelial injury in guinea pigs. The dose of 12c that prolonged the bleeding time to three times the control value was 5.8 microg/mL/min. These results suggest that compound 12c might be useful in the clinical treatment of thrombotic diseases, and we selected 12c (TAK-024) as a candidate for the clinical trials.