Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate

Abstract

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.

Identification of 6-Hydroxypyrimidin-4(1H)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists

“…Tertiary benzyl amide 5 demonstrated a nearly 10-fold increase in potency relative to secondary amide 4 . Further leveraging the SAR developed in the oxadiazole series, we found that phenyl substitution with a p -chloro group utilizing an ethyl linker to the amide ( 6 ) led to a further 10-fold increase in potency. The constrained phenyl-substituted pyrrolidine amides 7a ( R isomer) and 7b ( S isomer) without any substitution provided a 5-fold potency improvement compared with 6 .…”

“…The APJ receptor plays a role in regulating cardiovascular functions involved in HF and is activated by its endogenous ligands apelin and elabela. − Apelin is secreted as a 77 amino acid preproprotein and is rapidly cleaved to shorter biologically active fragments. − Of those, (Pyr 1 )­apelin-13 peptide is the most abundant fragment in the myocardium and plasma and demonstrates strong binding affinity for the receptor ( h APJ K d = 4.5 nM) and functional activity ( h APJ EC 50 = 0.06 nM and r APJ EC 50 = 0.07 nM). − Activation of the APJ receptor using (Pyr 1 )­apelin-13 improved cardiovascular function in HF animal models and clinically in HF r EF subjects. ,− Nevertheless, the therapeutic use of (Pyr 1 )­apelin-13 has been limited because of its plasma instability and the requirement of parenteral administration. , Significant effort has been made to identify orally active APJ agonists, including small molecules. − AMG 986 (Figure ) was reported to improve stroke volume and EF in an acute rat model of diastolic dysfunction and was advanced to clinical trials. , …”

“…Subsequently we disclosed aryl hydroxy pyrimidinones, which were further optimized, leading to the identification of hydroxy pyrimidinone compound 1 (BMS-986224) (Figure ). Compound 1 demonstrated robust pharmacodynamic effects in an acute rat pressure–volume (PV) loop model and was advanced as a clinical candidate . Herein we disclose a series of structurally differentiated 6-hydroxypyrimidin-4­(1 H )-one-3-carboxamides that have pharmacokinetic properties and pharmacodynamic effects comparable to those of compound 1 .…”

“…We were pleased to find that pyrimidinones 8a and 8b were more potent than pyridinones 7a and 7b . In an effort to increase microsomal stability, we incorporated the previously identified more polar C2 ethoxymethyl side chain . The resulting compound 9 did show improved metabolic stability in rat liver microsomes with a slight decrease of potency, but the PAMPA permeability was reduced.…”

“…We incorporated the p -Cl SAR identified previously to give compounds 10a and 10b , respectively. However, both isomers had decreased metabolic stability in rat liver microsomes without a significant improvement of potency compared with 8a and 8b .…”