title: The P2Y1 receptor antagonist MRS2500 prevents carotid artery thrombosis in cynomolgus monkeys.
abstract: Adenosine diphosphate directly induces platelet aggregation via the G-protein coupled P2Y1 and P2Y12 receptors. P2Y12, but not P2Y1, receptor antagonists are available in the clinic. The relevance of the P2Y1 receptor as an antiplatelet target has been studied in rodents, but not in higher species. We therefore examined effects of the pharmacological blockade of the P2Y1 receptor with its selective antagonist MRS2500 in monkey models of electrolytic-mediated arterial thrombosis (ECAT) and kidney bleeding time (KBT). Abciximab, a GPIIb-IIIa antagonist, and cangrelor, a P2Y12 antagonist, were utilized to validate these monkey models. Compounds were given IV at 15-60 min before thrombosis initiation in anesthetized monkeys. Scanning electron microscopy showed the luminal surface of thrombotic artery covered with platelet aggregates and fibrin network. Administration of abciximab at 0.25 and 0.7 mg/kg IV significantly reduced thrombus weight by 71 ± 1 and 100 ± 0 %, and increased KBT by 10.0 ± 0.1- and 10.1 ± 0-fold, respectively (n = 3/dose). Likewise, cangrelor at 0.6 and 2 mg/kg/h IV significantly reduced thrombus weight significantly by 72 ± 9 % and 100 ± 0 % and increased KBT by 2.1 ± 0.1- and 9.8 ± 0.2-fold, respectively (n = 3/dose). MRS2500 [mg/kg + mg/kg/h IV] at 0.09 + 0.14 and 0.45 + 0.68 significantly reduced thrombus weight by 57 ± 1 % and 88 ± 1 % and increased KBT by 2.1 ± 0.3- and 4.9 ± 0.6-fold, respectively (n = 4/dose). In summary, MRS2500 prevented occlusive arterial thrombosis at a dose that moderately prolonged KBT, indicating a role of P2Y1 receptors in arterial thrombosis and hemostasis in monkeys. Thus P2Y1 receptor antagonism provides a suitable target for drug discovery.
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA. pancras.wong@bms.com.
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Watson
authors.affiliation: Cardiovascular Drug Discovery Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ, 08534, USA.
authors.forename: Earl J
authors.initials: EJ
authors.lastname: Crain
mesh_terms: D000818:Animals; D002339:Carotid Arteries; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D008252:Macaca fascicularis; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology*; D013927:Thrombosis / Q000517:prevention & control*
chemical_list: C495475:2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate; D003838:Deoxyadenine Nucleotides; D058912:Purinergic P2Y Receptor Agonists
keywords: Abciximab; Antiplatelet; Cangrelor; Hemostasis; MRS2500; Nonhuman primates; Thrombosis