A patent review of apelin receptor (APJR) modulators (2014-2019)

ABSTRACT

Introduction: The apelinergic system is regarded as a novel therapeutic target for cardiovascular health, fluid homeostasis, the hypothalamic-pituitary-adrenal (HPA) axis as well as carbohydrate and fat metabolism. Two endogenous peptide ligands, namely apelin and elabela, have been demonstrated to moderate its various metabolic and neurological functions. Both bind with high (sub)-nanomolar affinity to APJR but get degraded rapidly in circulation. In addition, various diseases have been associated with the depletion of these regulatory peptides. Besides blocking the degrading proteases, a common strategy in targeting drugs to APJR is the development of metabolically stable peptide analogs or small molecule modulators. Supporting this trend, patent literature has evolved from 121 patents in 2014 to a total of almost 1000 patents today.

Areas covered: This review includes WIPO-listed small molecule and peptide-based agonists, antagonists and allosteric modulators of APJR published between 2014 and 2019.

Expert opinion: Both apelin peptide analogues and small molecule modulators are emerging, only recently including one example of an elabela-based analogue. Patent activity is predominantly on agonistic modulators since they show higher affinity and fewer off-target effects. Although several low nanomolar binders with half-lives exceeding 24 h have been confirmed in animal models, clinical validation of these drug-targets is sparse.

KEYWORDS:

• Apelin
• elabela
• APJ
• heart disease
• renin-angiotensin-aldosterone system
• peptide-based therapy

Article highlights

• Apelinergic system with endogenous ligand hormones apelin and elabela are important regulators of cardiac health, the HPA axis as well as fat and energy metabolism

• Majority of patent activity is focused on small molecule agonists and apelin mimetics with increased metabolic stability and physiological potency

• Patents include (sub)nanomolar binders as therapeutic agents for various acute and chronic cardiovascular diseases and diabetes

• First clinical studies involving apelin receptor modulators are emerging but generally still sparse

• Novel peptidomimetics could reflect highly selective drug targets for cardiovascular and metabolic diseases with reduced adverse effects

This box summarizes key points contained in the article.

Acknowledgments

The author would like to thank Matthew Schaefer (B.A.) for comments and a thorough spell-check.

Declaration of interest

C Fischer has shares in PEARKO Therapeutics Inc. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.