Negative allosteric modulators of group II metabotropic glutamate receptors: A patent review (2015 – present)

ABSTRACT

Introduction

Group II metabotropic glutamate (mGlu) receptors have emerged as an attractive potential target for the development of novel CNS therapeutics in areas such as Alzheimer’s disease (AD), anxiety, cognitive disorders, depression, and others. Several small molecules that act as negative allosteric modulators (NAMs) on these receptors have demonstrated efficacy and/or target engagement in animal models, and one molecule (decoglurant) has been advanced into clinical trials.

Areas covered

This review summarizes patent applications published between January 2015 and November 2020. It is divided into three sections: (1) small molecule nonselective mGlu_2/3 NAMs, (2) small molecule selective mGlu₂ NAMs, and (3) small molecule selective mGlu₃ NAMs.

Expert Opinion

Much progress has been made in the discovery of novel small molecule mGlu₂ NAMs. Still, chemical diversity remains somewhat limited and room for expansion remains. Progress with mGlu₃ NAMs has been more limited; however, some promising molecules have been disclosed. The process of elucidating the precise role of each receptor in the diseases associated with group II receptors has begun. Continued studies in animals with selective NAMs for both receptors will be critical in the coming years to inform researchers on the right compound profile and patient population for clinical development.

KEYWORDS:

• Decoglurant
• metabotropic glutamate receptor subtype 2
• metabotropic glutamate receptor subtype 3
• negative allosteric modulator
• Alzheimer’s disease
• anxiety
• cognition
• depression

Article Highlights

• The antidepressant effect of group II mGlu NAMs is of particular interest; however, there is not yet a consensus as to which receptor subtype is most critical for antidepressant effects.

• The mGlu_2/3 NAM decoglurant has advanced to clinical trials, and while it was well tolerated, it failed to demonstrate antidepressant or procognitive effects in humans that differentiated from placebo.

• A distinct trend toward the discovery of subtype selective NAMs has been observed in recent patent applications with most of the publications centered on the mGlu₂ receptor.

• Multiple assignees have disclosed similar scaffolds with similar functional group substitution patterns.

Additional selectivity and in vivo studies are still needed to establish the full utility of the disclosed compounds as probes or as lead compounds.

This box summarizes key points contained in the article.

Declaration of interest

KA Emmitte is an employee of the University of North Texas Health Science Center and receives funding from the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health. KA Emmitte is an inventor on multiple issued patents concerning small molecule allosteric modulators of metabotropic glutamate receptors. The authors have no other 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 funded by The University of North Texas Health Science Center.