N-Methyl-D-Aspartate (NMDA) receptor modulators: a patent review (2015-present)

ABSTRACT

Introduction

– The NMDA receptor is implicated in various diseases including neurodegenerative, neurodevelopmental and mood disorders. However, only a limited number of clinically approved NMDA receptor modulators are available. Today, apparent NMDA receptor drug development strategies entail 1) exploring the unknown chemical space to identify novel scaffolds; 2) using the clinically available NMDA receptor modulators to expand the therapeutic indication space; 3) and to trace physiological functions of the NMDA receptor.

Areas covered

– The current review reflects on the functional and pharmacological facets of NMDA receptors and the current clinical status quo of NMDA receptor modulators. Patent literature covering 2015 till April 2020 is discussed with emphasis on new indications.

Expert opinion

– Supporting evidence shows that subtype-selective NMDA receptor antagonists show an improved safety profile compared to broad-spectrum channel blockers. Although GluN2B-selective antagonists are by far the most extensively investigated subtype-selective modulators, they have shown only modest clinical efficacy so far. To overcome the limitations that have hampered the clinical development of previous subtype-selective NMDA receptor antagonists, future studies with improved animal models that better reflect human NMDA receptor pathophysiology are warranted. The increased availability of subtype-selective probes will allow target engagement studies and proper dose finding in future clinical trials.

KEYWORDS:

• NMDA receptor modulators
• neurodegenerative diseases
• mood disorders
• peripheral NMDA receptors
• glun2b subunits
• excitotoxicity
• pulmonary hypertension
• gaucher
• alzheimer’s
• glutamate
• multiple sclerosis

Article highlights

• An overview of the NMDA receptor machinery, subunit architecture, and related pathophysiology is provided.

• A summary of key therapeutic classes developed so far as well as representative ligands are delineated.

• Clinical development efforts as well as patents are focused on repurposing of the few clinically approved drugs available such as D-serine, ketamine, and memantine.

• GluN1/GluN2B modulators are by far the most patented class of compounds with 19 patents being filed/approved over the past five years. This period also witnessed major breakthroughs in developing PET imaging agents for imaging GluN1/GluN2B.

• With the emergence of new pharmacological tools, the role and therapeutic relevance of GluN1/GluN3 are being unraveled.

• Novel indications described include multiple sclerosis and Gaucher’s disease.

This box summarizes key points contained in the article.

Declaration of interest

The authors have 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

A reviewer on this manuscript has disclosed that they have pending patents in the subject matter area, are a co-founder of NeurOp Inc, which works on NMDA receptors, a SAB member of Sage Therapeutics which works on NMDA receptors, a paid consultant for Janssen, and the PI of grants from Biogen, Janssen, and Allergan. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.