Development of a Novel, Reversible P2Y12 Antagonist

描述(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经被很好地记录下来，因此在过去的十年中，血小板代表了治疗干预的主要靶点。本申请(FastTrack阶段L/11组合)旨在开发一种新型的P2Y12拮抗剂(血小板上的腺苷二磷酸受体，也是有效的药物靶点)，该药将克服氯吡格雷的局限性，氯吡格雷是一种已获批准的不可逆转的P2Y12抑制剂，需要肝脏代谢才能产生活性中间体。我们已经确定了一种直接作用的、可逆的P2Y12拮抗剂CT57537，它对该受体具有高效力和良好的药代动力学特性(合适的半衰期，低清除度，在多种物种中具有良好的口服生物利用度)。在这一阶段的应用中，我们将(1)确定CT57537在人和啮齿动物体外和体内血栓形成模型中是否具有抗血栓作用。为此，我们将使用(A)人和(B)小鼠全血在动脉剪切下通过胶原涂层毛细血管灌流和(C)在小鼠肠系膜动脉FeCIS诱导的在体损伤模型中测定CT57537的效力。其次，我们将在大鼠血栓形成模型中比较CT57537和氯吡格雷的抗血栓/止血比率，并将体内抗血栓效果与多个药物剂量下对体外血小板聚集的抑制相关联。第一阶段的成功完成将使我们能够继续进行第二阶段的研究，在该阶段，我们将在犬血栓形成模型中评估该化合物，评估P2Y12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，并使用CT57537完成必要的毒理学研究，以提交IND。

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.