Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ
| Autor: | Neil T. Burford, Marta Dabros, Mujing Yan, Michael C. Myers, Robert Langish, Cullen L. Cavallaro, R. Michael Lawrence, Shun Su, Ruth R. Wexler, Akbar Nayeem, Yi-Xin Li, Anne Rose, Chao Hannguang J, Peter S. Gargalovic, Kamelia Behnia, Bilder Donna M, Tao Wang, Joelle M. Onorato |
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| Rok vydání: | 2019 |
| Předmět: |
Agonist
Stereochemistry medicine.drug_class Clinical Biochemistry Pharmaceutical Science Pyrimidinones 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Humans Receptor Molecular Biology G protein-coupled receptor Apelin Receptors Molecular Structure 010405 organic chemistry Chemistry Aryl Organic Chemistry Small molecule In vitro 0104 chemical sciences Apelin High-Throughput Screening Assays 010404 medicinal & biomolecular chemistry HEK293 Cells Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry letters. 30(7) |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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