A lead generation campaign identified indole-based sPLA2-X inhibitors with a promising selectivity profile against other sPLA2 isoforms. Further optimization of sPLA2 selectivity and metabolic stability resulted in the design of (-)-17, a novel, potent, and selective sPLA2-X inhibitor with an exquisite pharmacokinetic profile characterized by high absorption and low clearance, and low toxicological risk. Compound (-)-17 was tested in an ApoE-/- murine model of atherosclerosis to evaluate the effect of reversible, pharmacological sPLA2-X inhibition on atherosclerosis development. Despite being well tolerated and achieving adequate systemic exposure of mechanistic relevance, (-)-17 did not significantly affect circulating lipid and lipoprotein biomarkers and had no effect on coronary function or histological markers of atherosclerosis.

中文翻译：

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选择性sPLA2-X抑制剂（-）-2- {2- [氨基甲酰基-6-（三氟甲氧基）-1H-吲哚-1-基]吡啶-2-基}丙酸的设计。

一项领先的研究活动确定了基于吲哚的sPLA2-X抑制剂具有针对其他sPLA2同工型的有希望的选择性。sPLA2选择性和代谢稳定性的进一步优化导致了（-）-17的设计，这是一种新颖，有效且选择性的sPLA2-X抑制剂，具有精致的药代动力学特征，具有高吸收，低清除率和低毒理学风险。在动脉粥样硬化的ApoE-/-鼠模型中测试了化合物（-）-17，以评估可逆的药理性sPLA2-X抑制对动脉粥样硬化发展的影响。尽管耐受性良好，并获得了与系统相关的充分系统暴露，但（-）-17并未显着影响循环脂质和脂蛋白生物标记，对冠状动脉功能或动脉粥样硬化的组织学标记没有影响。