Identification of 6-hydroxy-5-phenyl sulfonylpyrimidin-4(1H)-one APJ receptor agonists. (15th October 2021)

• Record Type: Journal Article
• Authors: Tora, George; Jiang, Ji; Bostwick, Jeffrey S.; Gargalovic, Peter S.; Onorato, Joelle M.; Luk, Chiuwa E.; Generaux, Claudia; Xu, Carrie; Galella, Michael A.; Wang, Tao; He, Yan; Wexler, Ruth R.; Finlay, Heather J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 50(2021)
• Publication Date: 2021-10-15
• Subjects: Apelin -- APJ receptor agonist -- [Pyr1]apelin-13 -- Sulfonylpyrimidine -- Heart failure; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128325
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Heart failure (HF) treatment remains a critical unmet medical need. Studies in normal healthy volunteers and HF patients have shown that [Pyr 1 ]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac function. However, the short half-life of [Pyr 1 ]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 [Pyr 1 ]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.