title: Inhibition of Factor XIa Reduces the Frequency of Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits.
abstract: 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 FeCl3injury 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 (ED50) 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 ED50levels 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.
authors.affiliation: 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.) wangxk2000@yahoo.com.
authors.forename: Xinkang
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Stan
authors.initials: S
authors.lastname: Kurowski
authors.affiliation: 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.).
authors.forename: Weizhen
authors.initials: W
authors.lastname: Wu
authors.affiliation: 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.).
authors.forename: Gino A
authors.initials: GA
authors.lastname: Castriota
authors.affiliation: 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.).
authors.forename: Xueping
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 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.).
authors.forename: Lin
authors.initials: L
authors.lastname: Chu
authors.affiliation: 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.).
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Ellsworth
authors.affiliation: 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.).
authors.forename: Donald
authors.initials: D
authors.lastname: Chu
authors.affiliation: 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.).
authors.forename: Scott
authors.initials: S
authors.lastname: Edmondson
authors.affiliation: 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.).
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.affiliation: 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.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Andre
authors.affiliation: 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.).
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seiffert
authors.affiliation: 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.).
authors.forename: Mark
authors.initials: M
authors.lastname: Erion
authors.affiliation: 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.).
authors.forename: David E
authors.initials: DE
authors.lastname: Gutstein
authors.affiliation: 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.).
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy; D004195:Disease Models, Animal; D015195:Drug Design; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D007275:Injections, Intravenous; D020766:Intracranial Embolism / Q000097:blood / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control; D008297:Male; D011817:Rabbits; D017585:Ultrasonography, Doppler, Transcranial / Q000379:methods
chemical_list: D000925:Anticoagulants; D015945:Factor XIa