Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation

Journal of Medicinal Chemistry
Andrew S FeltsKyle A Emmitte

Abstract

Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.

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Citations

Jul 6, 2021·Pharmacology, Biochemistry, and Behavior·Michael C SallingRichard W Foltin
May 30, 2020·Journal of the American Chemical Society·Jeffrey N LevyAndrew McNally
Jan 4, 2019·Organic Letters·Zhigao ShenLutz Ackermann
Feb 20, 2018·Journal of Medicinal Chemistry·Shaoyong Lu, Jian Zhang
Jun 20, 2018·Journal of Medicinal Chemistry·Dean G Brown, Jonas Boström

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Methods Mentioned

BETA
equilibrium dialysis
saturation binding
NMR

Software Mentioned

Agilent Chemstation
Analytical Studio Reviewer

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