Recent post hoc analyses of several clinical trials with P2Y₁₂ antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y₁₂ antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.

中文翻译：

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4-（（R）-2-{[[（（S）-3-甲氧基吡咯烷-1-基）-2-苯基嘧啶-4-羰基]氨基} -3-膦酰基丙酰基）哌嗪-1-甲酸丁酯（ACT-246475）及其前药（ACT-281959），与氯吡格雷相比，新型P2Y ₁₂受体拮抗剂在大鼠中的治疗范围更广

最近对P2Y ₁₂拮抗剂的几项临床试验的事后分析表明，需要新的分子作为抗血小板药充分有效，并且降低引起大出血的倾向。我们先前已经报道了在人类血浆中与疾病相关的血小板聚集试验中，具有纳摩尔浓度的P2Y ₁₂拮抗剂2-苯基嘧啶-4-羧酰胺类似物的发现。本文中，我们介绍了导致发现临床候选药物ACT-246475（30d）。关键步骤是用膦酸基团取代羧酸官能团，该膦酸基团提供了程序中最有效的分子。此外，首次在大鼠和狗中实现了较低的体内清除率。由于生物利用度30D为低在大鼠和狗，我们开发了双（（异丙氧基羰基）氧基）甲基酯前药（ACT-281959，45）。化合物30d在大鼠氯化铁血栓形成模型中以母体静脉给药或以其前药45口服时表现出功效。此外，与大鼠手术失血模型中的氯吡格雷相比，30d显示了更宽的治疗范围。