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
  • 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.
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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