Discovery of Thieno[3,2-<i>b</i>]pyridine-5-carboxamide and 2,3-Difluorobenzamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5
This Letter describes the discovery of novel mGlu<sub>5</sub> NAMs <b>VU6031545</b> and <b>VU6024945</b>. 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-<i>b</i>]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.
Authors
- Aaron M. Bender (ORCID: https://orcid.org/0000-0003-0432-1648)
- Alice L. Rodriguez (ORCID: https://orcid.org/0000-0002-5244-5103)
- Natasha B. Billard
- Changho Han (ORCID: https://orcid.org/0000-0002-0832-7070)
- David Whomble
- Kayla J. Temple (ORCID: https://orcid.org/0000-0001-5290-574X)
- Katherine J. Watson
- Scott H. Henderson (ORCID: https://orcid.org/0000-0002-9504-5943)
- Hyekyung P. Cho (ORCID: https://orcid.org/0000-0001-5393-2600)
- P. Jeffrey Conn (ORCID: https://orcid.org/0000-0003-2363-0323)
- Andrew S. Felts
- Katherine E. Crocker
- Colleen M. Niswender (ORCID: https://orcid.org/0000-0001-6009-8212)
- Jordan C. O’Neill
- Craig W. Lindsley (ORCID: https://orcid.org/0000-0003-0168-1445)
- Jerri M. Rook (ORCID: https://orcid.org/0000-0003-4029-0148)
- Anna L. Blobaum (ORCID: https://orcid.org/0000-0003-0349-7422)
- Rory A. Capstick
- Olivier G. Boutaud (ORCID: https://orcid.org/0000-0002-8910-0598)
- Julie L. Engers (ORCID: https://orcid.org/0009-0004-3654-5464)
- Mallory A. Maurer
- Sichen Chang
- Weimin Peng
Institutions
- Allen Institute for Brain Science (US)
- Vanderbilt University (US)
- Center for Discovery (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-04-22
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00119
- Citations
- 2
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- William K. Warren Foundation
- National Institutes of Health