mGlu₅ negative allosteric modulators: a patent review (2013 - 2016)

ABSTRACT

Introduction: The pursuit of small molecule mGlu₅ NAMs as treatments for a variety of psychiatric and neurodegenerative disorders has developed into a mature field. In addition to extensive preclinical studies, multiple compounds have advanced into clinical trials with the most advanced studies occurring in patients with FXS, PD-LID, and MDD.

Areas covered: This review begins with an update of the clinical activity with mGlu₅ NAMs, and then moves into a summary of patent applications filed since 2013. The summaries are organized into three separate sections: (1) inventions centered on improvements to existing clinical compounds; (2) new small molecules that maintain the prototypical disubstituted alkyne chemotype found in many mGlu₅ NAM compounds; and (3) new small molecules that are not from a disubstituted alkyne chemotype.

Expert opinion: It is a critical moment for mGlu₅ NAM research as recent reports from clinical trials have included some significant disappointments that have blunted prior optimism. Still, research in this area remains active, and recent years have added several more attractive small molecules to this field. There is now an arsenal of diverse chemotypes available to continue to probe this target in the hopes that a drug may yet emerge.

KEYWORDS:

• Basimglurant
• dipraglurant
• mavoglurant
• metabotropic glutamate receptor subtype 5
• negative allosteric modulator
• anxiety
• depression
• fragile X syndrome
• Parkinson’s disease
• levodopa-induced dyskinesia

Article highlights

• Recent results from phase II clinical studies with mGlu₅ NAMs have yielded disappointing outcomes in FXS patients and mixed results in PD and MDD patients.

• Some recent patent applications have focused on inventions related to improvements in drug properties and/or developability for the current crop of clinical compounds.

• Several new scaffolds containing the prototypical disubstituted alkyne moiety found in many previously published mGlu₅ NAMs have been disclosed in the patent literature in recent years.

• Continued development of chemical diversity within the mGlu₅ NAM field has been observed with recent patent applications.

• It is a critical time for the mGlu₅ NAM field, and clinical trials as well as preclinical toxicology studies have raised important questions.

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 North Texas Eye Research Institute. The author has 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 apart from those disclosed.

Additional information

Funding

This paper has been supported by the University of North Texas Health Science Center.