Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ. Issue 7 (1st April 2020)

• Record Type: Journal Article
• Authors: Myers, Michael C.; Bilder, Donna M.; Cavallaro, Cullen L.; Chao, Hannguang J.; Su, Shun; Burford, Neil T.; Nayeem, Akbar; Wang, Tao; Yan, Mujing; Langish, Robert A.; Dabros, Marta; Li, Yi-Xin; Rose, Anne V.; Behnia, Kamelia; Onorato, Joelle M.; Gargalovic, Peter S.; Wexler, Ruth R.; Lawrence, R. Michael
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 7(2020)
• Publication Date: 2020-04-01
• Subjects: Agonist -- APJ -- Atropisomer -- GPCR -- Heart failure; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.126955
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.