Development of a Novel, Reversible P2Y12 Antagonist

新型可逆 P2Y12 拮抗剂的开发

• 批准号: 6882155
• 负责人: PAMELA B CONLEY
• 金额: $ 10.01万
• 依托单位: PORTOLA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882155
• 关键词: adenosine diphosphate; antithrombins; cell surface receptors; clinical research; disease /disorder model; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; human tissue; inhibitor /antagonist; intravital microscopy; laboratory mouse; laboratory rat; pharmacokinetics; platelet aggregation inhibitors; purinergic receptor; thrombosis

DESCRIPTION (provided by applicant): The role of platelets in arterial thrombosis and cardiovascular disease has been well documented, and thus platelets have represented a major target of therapeutic intervention over the last decade. The present application (FastTrack Phase l/ll combination) is designed to develop a novel antagonist of P2Y12 (the ADP receptor on platelets and a validated drug target) that will overcome the limitations of clopidogrel, an approved irreversible, P2Y12 inhibitor that requires hepatic metabolism to generate the active intermediate. We have identified a direct-acting, reversible antagonist of P2Y12 called CT57537 that has high potency for this receptor and favorable pharmacokinetic properties (suitable half-life, low clearance, good oral bioavailability in multiple species). In this Phase I application, we will (1) determine whether CT57537 is antithrombotic in human and rodent ex vivo and in vivo models of thrombosis. To accomplish this, we will determine potency of CT57537 using (a) human and (b) mouse whole blood perfused through a collagen coated capillary under arterial shear and (c) in a mouse in vivo mesenteric artery FeCIS-induced injury model. Secondly, we will compare the antithrombotic/antihemostatic ratio for CT57537 to that of clopidogrel in a rat thrombosis model, and correlate in vivo antithrombotic efficacy with inhibition of ex vivo platelet aggregation at multiple drug doses. Successful completion of Phase I will allow us to proceed to Phase II studies where we will evaluate this compound in a canine model of thrombosis, evaluate the role of P2Y12 in platelet-mediated inflammatory events (plaque progression and neointimal proliferation), and complete the necessary toxicological studies with CT57537 necessary for filing an IND.

描述（由申请人提供）：血小板在动脉血栓形成和心血管疾病中的作用已得到充分证明，因此血小板在过去十年中已成为治疗干预的主要靶点。本申请（FastTrack I/II期组合）被设计为开发P2 Y12（血小板上的ADP受体和经验证的药物靶标）的新型拮抗剂，其将克服氯吡格雷的局限性，氯吡格雷是一种批准的不可逆的P2 Y12抑制剂，其需要肝脏代谢来产生活性中间体。我们已经鉴定了一种称为CT 57537的P2 Y12的直接作用的可逆拮抗剂，其对该受体具有高效力和有利的药代动力学性质（合适的半衰期、低清除率、在多个物种中良好的口服生物利用度）。在该I期申请中，我们将（1）确定CT 57537是否在人和啮齿动物离体和体内血栓形成模型中具有抗血栓形成作用。为了实现这一点，我们将使用（a）在动脉剪切下通过胶原包被的毛细管灌注的人和（B）小鼠全血和（c）在小鼠体内肠系膜动脉FeCIS诱导的损伤模型中测定CT 57537的效力。其次，我们将在大鼠血栓形成模型中比较CT 57537与氯吡格雷的抗血栓/抗止血比，并将体内抗血栓疗效与多个药物剂量下的离体血小板聚集抑制相关联。成功完成I期研究将使我们能够进行II期研究，我们将在犬血栓形成模型中评价该化合物，评价P2 Y12在血小板介导的炎症事件（斑块进展和新生内膜增殖）中的作用，并完成申报IND所需的CT 57537毒理学研究。