Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate
| Autor: | Heather Finlay, Claudia Generaux, Carrie Xu, Chiuwa E. Luk, Ruth R. Wexler, Ji Jiang, James A. Johnson, Michael Galella, Jeffrey S. Bostwick, William A. Schumacher, Tao Wang, Monique Phillips, Soong-Hoon Kim, Yan He, Joelle M. Onorato, Peter S. Gargalovic, Xue-Qing Chen, David A. Gordon |
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| Rok vydání: | 2021 |
| Předmět: |
Cardiac function curve
Agonist Male Models Molecular medicine.drug_class Pyridones Endogeny Pharmacology 01 natural sciences Rats Sprague-Dawley 03 medical and health sciences Dogs Drug Discovery medicine Animals Humans Receptor 030304 developmental biology Apelin receptor 0303 health sciences Apelin Receptors Chemistry Haplorhini medicine.disease 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry Heart failure Molecular Medicine Intercellular Signaling Peptides and Proteins |
| Zdroj: | Journal of medicinal chemistry. 64(6) |
| ISSN: | 1520-4804 |
| Popis: | Apelin-13 is an endogenous peptidic agonist of the apelin receptor (APJ) receptor with the potential for improving cardiac function in heart failure patients. However, the low plasma stability of apelin-13 necessitates continuous intravenous infusion for therapeutic use. There are several approaches to increase the stability of apelin-13 including attachment of pharmacokinetic enhancing groups, stabilized peptides, and Fc-fusion approaches. We sought a small-molecule APJ receptor agonist approach to target a compound with a pharmacokinetic profile amenable for chronic oral administration. This manuscript describes sequential optimization of the pyrimidinone series, leading to pyridinone |
| Databáze: | OpenAIRE |
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