In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.

中文翻译：

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N- [6-（4-丁酰基-5-甲基-1 H-吡唑-1-基）哒嗪-3-基] -5-氯-1- [2-（4-甲基哌嗪-1-基）-2 -氧乙基] -1 H-吲哚-3-羧酰胺（SAR216471），一种新型的静脉和口服，可逆和直接作用的P2Y12拮抗剂

为了寻找潜在的氯吡格雷后备药物，我们发起了旨在确定新型可逆P2Y12拮抗剂的HTS运动。从具有低微摩尔结合活性的命中开始，我们在此报告优化过程的主要步骤，这些步骤可导致临床前候选药物SAR216471的鉴定。它是一种有效，高度选择性和可逆的P2Y12受体拮抗剂，是迄今为止文献中描述的P2Y12拮抗剂中ADP诱导的血小板聚集的最有效抑制剂。SAR216471表现出强大的体内抗血小板和抗血栓形成活性，并且有可能与其他抗血小板药物区分开。