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.
- 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.
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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Cat. No.Product NameDescriptionTargetResearch Area
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target: mGluRResearch Areas: Neurological Disease
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target: mGluRResearch Areas: Neurological Disease