Identification of 6-hydroxy-5-phenyl sulfonylpyrimidin-4(1H)-one APJ receptor agonists

doi:10.1016/j.bmcl.2021.128325

Bioorganic & Medicinal Chemistry Letters

Volume 50, 15 October 2021, 128325

https://doi.org/10.1016/j.bmcl.2021.128325 Get rights and content

Abstract

Heart failure (HF) treatment remains a critical unmet medical need. Studies in normal healthy volunteers and HF patients have shown that [Pyr¹]apelin-13, the endogenous ligand for the APJ receptor, improves cardiac function. However, the short half-life of [Pyr¹]apelin-13 and the need for intravenous administration have limited the therapeutic potential for chronic use. We sought to identify potent, small-molecule APJ agonists with improved pharmaceutical properties to enable oral dosing in clinical studies. In this manuscript, we describe the identification of a series of pyrimidinone sulfones as a structurally differentiated series to the clinical lead (compound 1). Optimization of the sulfone series for potency, metabolic stability and oral bioavailability led to the identification of compound 22, which showed comparable APJ potency to [Pyr¹]apelin-13 and exhibited an acceptable pharmacokinetic profile to advance to the acute hemodynamic rat model.

Graphical abstract

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Notes

The supporting information is available separately.

Crystallographic data for Compound 22 has been deposited to CCDC and the deposit number is 2083087.

All authors have given approval to the final version of the manuscript.

The authors were employed by Bristol Myers Squibb at the time of this work and some authors may own stock.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Elabela (ELA), Apela or Toddler peptide is a hormone peptide belonging to the adipokine group and a component of apelinergic system, discovered in 2013–2014. Given its high homology with apelin, the first ligand of APJ receptor, ELA likely mediates similar effects. Increasing evidence shows that ELA has a critical function not only in embryonic development, but also in adulthood, contributing to physiological and pathological conditions, such as the onset of age-related diseases (ARD). However, still little is known about the mechanisms and molecular pathways of ELA, as well as its precise functions in ARD pathophysiology. Here, we report the mechanisms by which ELA/APJ signaling acts in a very complex network of pathways for the maintenance of physiological functions of human tissue and organs, as well as in the onset of some ARD, where it appears to play a central role. Therefore, we describe the possibility to use the ELA/APJ pathway, as novel biomarker (predictive and diagnostic) and target for personalized treatments of ARD. Its potentiality as an optimal peptide candidate for therapeutic ARD treatments is largely described, also detailing potential current limitations.
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Apelin and Elabela (Ela) are peptides encoded by APLN and APELA, respectively, which act on their receptor APJ and play crucial roles in the body. Recent research has shown that they not only have important effects on the endocrine system, but also promote vascular development and maintain the homeostasis of myocardial cells. From a molecular biology perspective, we explored the roles of Ela and apelin in the cardiovascular system and summarized the mechanisms of apelin-APJ signaling in the progression of myocardial infarction, ischemia-reperfusion injury, atherosclerosis, pulmonary arterial hypertension, preeclampsia, and congenital heart disease. Evidences indicated that apelin and Ela play important roles in cardiovascular diseases, and there are many studies focused on developing apelin, Ela, and their analogues for clinical treatments. However, the literature on the therapeutic potential of apelin, Ela and their analogues and other APJ agonists in the cardiovascular system is still limited. This review summarized the regulatory pathways of apelin/ELA-APJ axis in cardiovascular function and cardiovascular-related diseases, and the therapeutic effects of their analogues in cardiovascular diseases were also included.
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Heart failure is one of the most significant public health problems faced by millions of medical researchers worldwide. And pathological cardiac hypertrophy is considered one of the possible factors of increasing the risk of heart failure. Here, we introduce apelin/ELABELA-APJ system as a novel therapeutic target for cardiac hypertrophy, bringing about new directions in clinical treatment. Apelin has been proven to regulate cardiac hypertrophy through various pathways. And an increasing number of studies on ELABELA, the newly discovered endogenous ligand, suggest it can alleviate cardiac hypertrophy through mechanisms similar or different to apelin. In this review, we elaborate on the role that apelin/ELABELA-APJ system plays in cardiac hypertrophy and the intricate mechanisms that apelin/ELABELA-APJ affect cardiac hypertrophy. We also illuminate and make comparisons of the newly designed peptides and small molecules as agonists and antagonists for APJ, updating the breakthroughs in this field.
Synthesis and characterization of an orally bioavailable small molecule agonist of the apelin receptor
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Citation Excerpt :
Based on these observations, there is strong interest in developing small molecule regulators of this receptor for cardiovascular diseases and other related indications. To date, two small molecule clinical candidates from Amgen (AMG 986) and Bristol-Myers Squibb (BMS-986224) leading up to Phase 1 evaluation of apelinergic compounds in humans were reported.7–18 Several other preclinical programs are also in advanced stages.19–22
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To this end, it has been demonstrated that another compound, BMS-986224, has physiological effects resembling [pyr1]-apelin-13 and drug-like properties when administered orally to animals with HF [250]. 6-hydroxy-5-phenyl sulfonylpyrimidin-4(1 H)-one is yet another oral candidate that, when administered to the acute hemodynamic rat model, significantly improves cardiac output without affecting BP and heart rate [251]. Since β-arrestin recruitment may be linked to receptor desensitization and internalization, CMF-019, the first G-protein biased ApelinR agonist (approximately 400-fold), emerged as a scaffold to prevent receptor tachyphylaxis [252].
The apelin/apelin receptor (ApelinR) signal transduction pathway exerts essential biological roles, particularly in the cardiovascular system. Disturbances in the apelin/ApelinR axis are linked to vascular, heart, kidney, and metabolic disorders. Therefore, the apelinergic system has surfaced as a critical therapeutic strategy for cardiovascular diseases (including pulmonary arterial hypertension), kidney disease, insulin resistance, hyponatremia, preeclampsia, and erectile dysfunction. However, apelin peptides are susceptible to rapid degradation through endogenous peptidases, limiting their use as therapeutic tools and translational potential. These proteases include angiotensin converting enzyme 2, neutral endopeptidase, and kallikrein thereby linking the apelin pathway with other peptide systems. In this context, apelin analogs with enhanced proteolytic stability and synthetic ApelinR agonists emerged as promising pharmacological alternatives. In this review, we focus on discussing the putative roles of the apelin pathway in various physiological systems from function to dysfunction, and emphasizing the therapeutic potential of newly generated metabolically stable apelin analogs and non-peptide ApelinR agonists.
The Apelin/APJ System: A Potential Therapeutic Target for Sepsis
2024, Journal of Inflammation Research

¹: These authors contribute equally to this manuscript.

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Identification of 6-hydroxy-5-phenyl sulfonylpyrimidin-4(1H)-one APJ receptor agonists

Abstract

Graphical abstract

Section snippets

Notes

Declaration of Competing Interest

Trends Pharmacol Sci

J Am Coll Cardiol

Reg Pep

Heart failure with reduced ejection fraction: a review

JAMA

National trends in heart failure hospital stay rates, to 2009

J Am Coll Cardiol

Epidemiology and aetiology of heart failure

Nat Rev Cardiol

Myint Do patient have worse outcome in heart failure than in cancer? a primary care-based cohore study wit 10-year follow-up in Scotland

Eur J Heart Fail

Laufs Heart failure with preserved ejection fraction: Current management and future strategies: expert opinion on the behalf of the Nucleus of the “Heart Failure Working Group” of the German Society of Cardiology (DKG)

Clin Res Cardiol

Diuretic therapy in heart failure – current approaches

Euro Cardiol.

Agents with inotropic properties for the management of acute heart failure syndromes. Traditional agents and beyond

Heart Fail Rev