mGluR2 positive allosteric modulators: an updated patent review (2013–2018)

ABSTRACT

Introduction: Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research.

Areas covered: 2013–2018 patent literature on mGlu2 receptor PAMs.

Expert opinion: After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.

KEYWORDS:

• Metabotropic glutamate receptor 2
• mGlu2
• positive allosteric modulator
• PAM

Article highlights

• The mGlu2 receptor has emerged as a novel therapeutic target for the treatment of central nervous system disorders characterized by a glutamatergic dysfunction.

• The difficulties encountered with mGlu2 receptor orthosteric agonists, such as lack of sub-type selectivity, poor central nervous system penetration, and receptor desensitization spurred the research on positive allosteric modulators as an alternative to address overcome those issues.

• To date, two mGlu2 receptor PAM molecules have entered clinical trials: AZD8529 from AstraZeneca and JNJ-40411813 (also known as ADX71149) from Janssen Pharmaceuticals, Inc. and Addex Therapeutics.

• Although both compounds failed to show robust efficacy in POC Phase 2a studies in schizophrenia and major depressive disorders, preclinical data suggest the utility of mGlu2 PAMs for smoking cessation and in epilepsy, which may open novel potential therapeutic avenues for this mechanism of action.

• In spite of the fact that the clinical failures have tempered the high expectations set on the mGlu2 receptor activation mechanism for treating psychiatric disorders, the interest on mGlu2 receptor PAMs remains high and in the period covered by this review (2013–2018) 16 new patent applications from seven different pharmaceutical companies and institutions have been submitted.

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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

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

Additional information

Funding

This paper was not funded.