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Updated: Jun 4, 2025

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic
Elizabeth S Childress1,2, Rory A Capstick1,2, Katherine E Crocker1,2
1Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
Abstract:
This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu5) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified VU6043653, a highly brain penetrant and selective mGlu5 NAM which displayed moderate potency against both human and rat mGlu5. Moreover, VU6043653 has overall improved pharmacological and drug metabolism and pharmacokinetic profiles when compared to its predecessor compounds. Most notably, VU6043653 exhibits low predicted human hepatic clearance, a clean cytochrome P450 profile, and minimal inhibition of the dopamine transporter.
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