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

Autor: Myers MC; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States. Electronic address: michael.myers@bms.com., Bilder DM; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Cavallaro CL; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Chao HJ; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Su S; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Burford NT; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Nayeem A; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Wang T; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Yan M; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Langish RA; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Dabros M; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Li YX; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Rose AV; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Behnia K; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Onorato JM; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Gargalovic PS; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Wexler RR; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States., Lawrence RM; Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, NJ 08543, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Apr 01; Vol. 30 (7), pp. 126955. Date of Electronic Publication: 2020 Jan 22.
DOI: 10.1016/j.bmcl.2020.126955
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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