Heart failure (HF) treatment remains a critical unmet medical need. Studies in normal healthy volunteers and HF patients have shown that [Pyr¹]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac function. However, the short half-life of [Pyr¹]apelin-13 and the need for intravenous administration have limited the therapeutic potential for chronic use. We sought to identify potent, small-molecule APJ agonists with improved pharmaceutical properties to enable oral dosing in clinical studies. In this manuscript, we describe the identification of a series of pyrimidinone sulfones as a structurally differentiated series to the clinical lead (compound 1). Optimization of the sulfone series for potency, metabolic stability and oral bioavailability led to the identification of compound 22, which showed comparable APJ potency to [Pyr¹]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.

心力衰竭 (HF) 治疗仍然是一项未满足的重要医疗需求。对正常健康志愿者和 HF 患者的研究表明，APJ 受体的内源性配体[Pyr ¹ ]apelin-13 可改善心脏功能。然而，[Pyr ¹ ]apelin-13的短半衰期和需要静脉内给药限制了长期使用的治疗潜力。我们试图确定具有改进药学特性的强效小分子 APJ 激动剂，以便在临床研究中进行口服给药。在这份手稿中，我们描述了一系列嘧啶酮砜作为临床先导药物的结构差异系列（化合物1）。砜系列的效力、代谢稳定性和口服生物利用度的优化导致化合物22的鉴定，其显示出与 [Pyr ¹ ]apelin-13相当的 APJ 效力，并显示出可接受的药代动力学特征以推进急性血流动力学大鼠模型。