2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Jun 22;60(12):5072-5085. doi: 10.1021/acs.jmedchem.7b00410.
Andrew S Felts,  Alice L Rodriguez,  Anna L Blobaum,  Ryan D Morrison,  Brittney S Bates,  Analisa Thompson Gray,  Jerri M Rook,  Mohammed N Tantawy 1,  Frank W Byers,  Sichen Chang,  Daryl F Venable,  Vincent B Luscombe,  Gilles D Tamagnan 2,  Colleen M Niswender,  J Scott Daniels,  Carrie K Jones,  P Jeffrey Conn,  Craig W Lindsley,  Kyle A Emmitte
Affiliations

Affiliations

  • 1 Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
  • 2 Molecular NeuroImaging, a Division of inviCRO , New Haven, Connecticut 06510, United States.
PMID: 28530802 DOI: 10.1021/acs.jmedchem.7b00410
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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