Optimization of AZD6482 (2), the first antiplatelet PI3Kβ inhibitor evaluated in man, focused on improving the pharmacokinetic profile to a level compatible with once daily oral dosing as well as achieving adequate selectivity towards PI3Kα to minimize the risk for insulin resistance. Structure-based design and optimization of DMPK properties resulted in (R)-16, a novel, orally bioavailable PI3Kβ inhibitor with potent in vivo anti-thrombotic effect with excellent separation to bleeding risk and insulin resistance.

中文翻译：

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发现9-（1-苯氧基乙基）-2-吗啉代-4-氧代-吡啶并[1,2 - a ]嘧啶-7-羧酰胺为口服PI3Kβ抑制剂，可用作抗血小板药

对AZD6482（2）的优化是第一个在人体中评估的抗血小板PI3Kβ抑制剂，其重点是将药代动力学曲线提高至与每日一次口服给药相适应的水平，并实现对PI3Kα的选择性，以最大程度地降低胰岛素抵抗的风险。基于结构的设计和DMPK特性的优化产生了（R）-16，这是一种新型的口服生物利用的PI3Kβ抑制剂，具有有效的体内抗血栓形成作用，对出血风险和胰岛素抵抗的分离效果极好。