Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 6, Pages 3086-3099Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01878
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- Bristol Myers Squibb
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In this study, a small-molecule APJ receptor agonist, compound 14, was developed with excellent oral bioavailability and pharmacokinetic properties. Compound 14 displayed in vitro potency equivalent to apelin-13 and robust pharmacodynamic effects in preclinical models, making it a promising clinical candidate.
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 14, with in vitro potency equivalent to the endogenous ligand apelin-13 and with an excellent oral bioavailability and PK profile in multiple preclinical species. Compound 14 exhibited robust pharmacodynamic effects similar to apelin-13 in an acute rat pressure-volume loop model and was advanced as a clinical candidate.
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