2. Academic Validation
  3. Discovery of Thieno[3,2- b]pyridine-5-carboxamide and 2,3-Difluorobenzamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Discovery of Thieno[3,2- b]pyridine-5-carboxamide and 2,3-Difluorobenzamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

  • ACS Med Chem Lett. 2025 Apr 22;16(5):865-874. doi: 10.1021/acsmedchemlett.5c00119.
Katherine E Crocker 1 2,  Scott H Henderson 1 2,  Rory A Capstick 1 2,  David L Whomble 1 2,  Aaron M Bender 1 2,  Andrew S Felts 1 2,  Changho Han 1 2,  Julie L Engers 1 2,  Natasha B Billard 1 2,  Mallory A Maurer 1 2,  Hyekyung P Cho 1 2,  Alice L Rodriguez 1 2,  Colleen M Niswender 1 2 3 4 5,  Jordan O'Neill 1 2,  Katherine J Watson 1 2,  Sichen Chang 1 2,  Anna L Blobaum 1 2,  Olivier Boutaud 1 2,  Weimin Peng 2,  Jerri M Rook 2,  P Jeffrey Conn 1 2 5,  Craig W Lindsley 1 2 6 3,  Kayla J Temple 1 2
Affiliations

Affiliations

  • 1 Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3 Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4 Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 5 Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 6 Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 40365396 DOI: 10.1021/acsmedchemlett.5c00119
Abstract

This Letter describes the discovery of novel mGlu5 NAMs VU6031545 and VU6024945. Starting from previously reported picolinamide compounds, a structure-activity relationship study of various core isosteres was conducted, leading to the identification of thieno[3,2-b]pyridine-5-carboxamide and 2,3-difluorobenzamide as competent core replacements. These compounds are highly potent as well as brain penetrant with an IVIVC agreement and improved oral bioavailability in rats.

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