Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton New Jersey 08543, United States.
J Med Chem. 2013 Feb 28;56(4):1704-14. doi: 10.1021/jm301708u. Epub 2013 Feb 18.
Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.
两种不同的 G 蛋白偶联嘌呤能受体 P2Y1 和 P2Y12 介导 ADP 驱动的血小板激活。P2Y12 阻断的临床疗效已得到充分证实。最近的临床前数据表明，P2Y1 和 P2Y12 的抑制作用提供了相当的抗血栓疗效，而靶向 P2Y1 则有可能降低出血风险。在本报告中，描述了发现一种 2-(苯氧基吡啶)-3-苯基脲化学型，可抑制人血液样本中的 ADP 介导的血小板聚集。对该系列的优化导致了化合物 16（1-(2-(2-叔丁基苯氧基)吡啶-3-基)-3-4-(三氟甲氧基)苯基脲）的鉴定，该化合物在已建立的大鼠动脉血栓形成模型中（10mg/kg 加 10mg/kg/h）可减少 68±7%的血栓重量，而在诱导的大鼠出血时间模型中，仅分别延长表皮和肠系膜出血时间 3.3 倍和 3.1 倍。这些结果表明，P2Y1 拮抗剂可能具有提供安全有效的抗血栓形成作用。
