Login / Signup

Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate.

James A JohnsonSoong-Hoon KimJi JiangMonique PhillipsWilliam A SchumacherJeffrey S BostwickPeter S GargalovicJoelle M OnoratoChiuwa E LukClaudia GenerauxYan HeXue-Qing ChenCarrie XuMichael A GalellaTao WangDavid A GordonRuth R WexlerHeather J Finlay
Published in: Journal of medicinal chemistry (2021)
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.
Keyphrases
  • small molecule
  • low dose
  • oxidative stress
  • bone marrow
  • risk assessment
  • respiratory failure
  • protein protein
  • hepatitis b virus
  • acute respiratory distress syndrome