Discovery of 7-(Pyridin-3-yl)thieno[3,2- <i>b</i> ]pyridine-5-carboxamides as Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Herein, we report the structure-activity relationship (SAR) to develop novel mGlu<sub>5</sub> negative allosteric modulator (NAM) scaffolds devoid of the aryl/heterobiaryl acetylene moiety found in many historic mGlu<sub>5</sub> NAMs, which has been linked to metabolic liabilities and hepatotoxicity. This endeavor utilized a scaffold-hopping strategy from the predecessor compound <b>VU6031545</b>, in which we replace an ether-linked tetrahydrofuran with various carbon-linked heteroaryl motifs to generate highly potent and selective mGlu<sub>5</sub> NAMs. One such compound, <b>VU6035386</b>, displayed low nanomolar potency against human mGlu<sub>5</sub> and was highly brain penetrant. Moreover, <b>VU6035386</b> showed a vast improvement in predicted human hepatic clearance versus predecessor compound <b>VU6031545</b>.

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Publication Details

Journal
ACS Chemical Neuroscience
Published
2026-01-26
DOI
https://doi.org/10.1021/acschemneuro.5c00896
Primary Topic
Neuroscience and Neuropharmacology Research
Type
article
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article

Discovery of 7-(Pyridin-3-yl)thieno[3,2- b ]pyridine-5-carboxamides as Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Alice L. Rodriguez, Natasha B. Billard, David Whomble, Kayla J. Temple et al.
ACS Chemical Neuroscience
Neuroscience and Neuropharmacology Research
article

Discovery of 7-(Pyridin-3-yl)thieno[3,2- b ]pyridine-5-carboxamides as Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5

Alice L. Rodriguez, Natasha B. Billard, David Whomble, Kayla J. Temple, Scott H. Henderson, Hyekyung P. Cho, Andrew S. Felts, Colleen M. Niswender, Anna L. Blobaum, Rory A. Capstick, Olivier G. Boutaud, Sri H. Kethanapalli, Mallory A. Maurer, Sichen Chang, Weimin Peng, Alexa E. Richardson, Xia Lei, Joshua C. Wilkinson, P. Jeffrey Conn, Jerri M. Rook, Anna E. Ringuette, Craig W. Lindsley
article en

Abstract

Herein, we report the structure-activity relationship (SAR) to develop novel mGlu<sub>5</sub> negative allosteric modulator (NAM) scaffolds devoid of the aryl/heterobiaryl acetylene moiety found in many historic mGlu<sub>5</sub> NAMs, which has been linked to metabolic liabilities and hepatotoxicity. This endeavor utilized a scaffold-hopping strategy from the predecessor compound <b>VU6031545</b>, in which we replace an ether-linked tetrahydrofuran with various carbon-linked heteroaryl motifs to generate highly potent and selective mGlu<sub>5</sub> NAMs. One such compound, <b>VU6035386</b>, displayed low nanomolar potency against human mGlu<sub>5</sub> and was highly brain penetrant. Moreover, <b>VU6035386</b> showed a vast improvement in predicted human hepatic clearance versus predecessor compound <b>VU6031545</b>.

ACS Chemical NeuroscienceVol. 17(3)
Allen Institute for Brain Science (US), Vanderbilt University (US), Institute of Chemical Biology and Fundamental Medicine (RU), Kennedy Center (DK), Health Advances (United States) (US), Center for Discovery (US), Vanderbilt University Medical Center (US)
Openalex Percentile: Top 79%
Neuroscience and Neuropharmacology Research
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