Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ

• Published in: Bioorganic & medicinal chemistry letters Vol. 30; no. 7; pp. 126955 - 126958
• Main 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
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2020; Elsevier
• Subjects: Agonist; Apelin Receptors - agonists; APJ; Atropisomer; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Discovery; GPCR; Heart failure; HEK293 Cells; High-Throughput Screening Assays; Humans; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacology; Science & Technology; Structure-Activity Relationship; Heart failure; GPCR; Agonist; APJ; Atropisomer; ANALOGS; APELIN; RECEPTOR; LIGAND
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2020.126955

[Display omitted] 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.