Wang Xinkang, Kurowski Stan, Wu Weizhen, Castriota Gino A, Zhou Xueping, Chu Lin, Ellsworth Kenneth P, Chu Donald, Edmondson Scott, Ali Amjad, Andre Patrick, Seiffert Dietmar, Erion Mark, Gutstein David E, Chen Zhu
Cardiometabolic Disease Biology (X.W., S.K., W.W., G.A.C., X.Z., P.A., D.S., M.E., D.E.G., Z.C.), Discovery Pharmaceutical Sciences (L.C.), In Vitro Pharmacology (K.E., D.C.), and Discovery Chemistry (S.E.), Merck Research Laboratories, Kenilworth, New Jersey; Lead Optimization Chemistry, Merck Research Laboratories, Rahway, New Jersey (A.A.)
Cardiometabolic Disease Biology (X.W., S.K., W.W., G.A.C., X.Z., P.A., D.S., M.E., D.E.G., Z.C.), Discovery Pharmaceutical Sciences (L.C.), In Vitro Pharmacology (K.E., D.C.), and Discovery Chemistry (S.E.), Merck Research Laboratories, Kenilworth, New Jersey; Lead Optimization Chemistry, Merck Research Laboratories, Rahway, New Jersey (A.A.).
J Pharmacol Exp Ther. 2017 Mar;360(3):476-483. doi: 10.1124/jpet.116.238600. Epub 2016 Dec 29.
Factor XI (FXI) is an integral component of the intrinsic pathway of the coagulation cascade and plays a critical role in thrombus formation. Because its role in the pathogenesis of cerebral microembolic signals (MES) is unclear, this study used a potent and selective small molecule inhibitor of FXIa, compound 1, to assess the effect of FXI blockade in our recently established preclinical model of cerebral MES induced by FeCl injury of the carotid artery in male New Zealand White rabbits. Ascending doses of compound 1 were evaluated simultaneously for both carotid arterial thrombosis by a Doppler flowmeter and MES in the middle cerebral artery by a transcranial Doppler. Plasma drug exposure and pharmacodynamic responses to compound 1 treatment were also assessed. The effective dose for 50% inhibition (ED) of thrombus formation was 0.003 mg/kg/h compound 1, i.v. for the integrated blood flow, 0.004 mg/kg/h for reduction in thrombus weight, and 0.106 mg/kg/h for prevention of MES. The highest dose, 3 mg/kg/h compound 1, achieved complete inhibition in both thrombus formation and MES. In addition, we assessed the potential bleeding liability of compound 1 (5 mg/kg/h, i.v., >1250-fold ED levels in arterial thrombosis) in rabbits using a cuticle bleeding model, and observed about 2-fold (not statistically significant) prolongation in bleeding time. Our study demonstrates that compound 1 produced a robust and dose-dependent inhibition of both arterial thrombosis and MES, suggesting that FXIa blockade may represent a novel therapeutic strategy for the reduction in MES in patients at risk for ischemic stroke.
凝血因子 XI（FXI）是凝血级联内源性途径的一个重要组成部分，在血栓形成中起关键作用。由于其在脑微栓塞信号（MES）发病机制中的作用尚不清楚，本研究使用一种强效且选择性的FXIa小分子抑制剂化合物1，在我们最近建立的雄性新西兰白兔颈动脉FeCl损伤诱导脑MES的临床前模型中，评估FXI阻断的效果。通过多普勒流量计同时评估递增剂量的化合物1对颈动脉血栓形成的影响，并通过经颅多普勒评估大脑中动脉的MES。还评估了血浆药物暴露情况以及对化合物1治疗的药效学反应。对血栓形成的50%抑制有效剂量（ED），对于综合血流量，静脉注射化合物1为0.003mg/kg/h，对于血栓重量减轻为0.004mg/kg/h，对于预防MES为0.106mg/kg/h。最高剂量3mg/kg/h的化合物1在血栓形成和MES方面均实现了完全抑制。此外，我们使用表皮出血模型评估了化合物1（5mg/kg/h，静脉注射，在动脉血栓形成中>1250倍ED水平）在兔中的潜在出血风险，观察到出血时间延长约2倍（无统计学意义）。我们的研究表明，化合物1对动脉血栓形成和MES均产生了强大且剂量依赖性的抑制作用，提示FXIa阻断可能代表一种降低缺血性中风风险患者MES的新治疗策略。
