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mGluR5 Negative Allosteric Modulators Overview: A Medicinal Chemistry Approach Towards a Series of Novel Therapeutic Agents

[ Vol. 11 , Issue. 6 ]


Jean-Philippe Rocher, Beatrice Bonnet, Christelle Bolea, Robert Lutjens, Emmanuel Le Poul, Sonia Poli, Mark Epping-Jordan, Anne-Sophie Bessis, Bernard Ludwig and Vincent Mutel   Pages 680 - 695 ( 16 )


Allosteric modulators of metabotropic glutamate receptors (mGluRs) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel and highly desirable class of compounds for the treatment of central nervous system (CNS) disorders and peripheral disorders. This article provides medicinal chemistry highlights around the chemical classes of potent and highly selective mGluR5 negative allosteric modulators (NAMs) and their therapeutic potential. In addition, it describes the medicinal chemistry approach from the discovery to the clinical candidate selection of a new series of heteroaryl-butynylpyridines targeting mGluR5. The multiparametric optimization of the initial starting point which ended in the selection of potential clinical candidates combining the best pharmacophoric features is presented. The pharmacological properties are reported and support the interest of these agents for new therapeutic approaches. Furthermore, a summary of the diverse mGluR5 Positron Emission Tomography (PET) radioligands is reported.


Glutamate, glutamate receptor, mGluR5, negative allosteric modulator, compounds, central nervous system (CNS) disorders, Positron Emission Tomography (PET), transduction mechanism, Parkinson's disease, fragile X syndrome, anxiety, gastro-esophageal acid reflux disease, turnover assay, SAR, potency


Addex Pharma SA, Core Chemistry Department, Chemin des Aulx 12, 1228 Plan-les-Ouates Geneva, Switzerland.

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