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

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.