This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

中文翻译：

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发现和SAR芳基羟基嘧啶酮作为GPCR APJ的有效小分子激动剂。

本文介绍了芳基羟基嘧啶酮的发现以及为有效APJ激动优化这种化学型的药物化学努力。APJ是一种G蛋白偶联受体，其天然激动剂肽apelin在心力衰竭患者的心脏功能中显示出血液动力学改善。进行了高通量筛选，以鉴定可优化以模拟apelin体外反应的小分子命中。通过优化HTS命中和药物化学努力以改善其性能，鉴定出了有效的低分子量芳基羟基嘧啶酮类似物30。