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Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. 2017
Andrew S Felts, and
Alice L Rodriguez, and
Ryan D Morrison, and
Katrina A Bollinger, and
Daryl F Venable, and
Anna L Blobaum, and
Frank W Byers, and
Analisa Thompson Gray, and
J Scott Daniels, and
Colleen M Niswender, and
Carrie K Jones, and
P Jeffrey Conn, and
Craig W Lindsley, and
Kyle A Emmitte
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu5 NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu5 versus DAT.
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Andrew S Felts, and
Alice L Rodriguez, and
Ryan D Morrison, and
Katrina A Bollinger, and
Daryl F Venable, and
Anna L Blobaum, and
Frank W Byers, and
Analisa Thompson Gray, and
J Scott Daniels, and
Colleen M Niswender, and
Carrie K Jones, and
P Jeffrey Conn, and
Craig W Lindsley, and
Kyle A Emmitte
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Ryan D Morrison, and
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Daryl F Venable, and
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J Scott Daniels, and
Colleen M Niswender, and
Carrie K Jones, and
P Jeffrey Conn, and
Craig W Lindsley, and
Kyle A Emmitte
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J Scott Daniels, and
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Carrie K Jones, and
P Jeffrey Conn, and
Craig W Lindsley, and
Kyle A Emmitte
January 2020,
Advances in pharmacology (San Diego, Calif.),
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Anna L Blobaum, and
Frank W Byers, and
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J Scott Daniels, and
Colleen M Niswender, and
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P Jeffrey Conn, and
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Andrew S Felts, and
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Ryan D Morrison, and
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Anna L Blobaum, and
Frank W Byers, and
Analisa Thompson Gray, and
J Scott Daniels, and
Colleen M Niswender, and
Carrie K Jones, and
P Jeffrey Conn, and
Craig W Lindsley, and
Kyle A Emmitte
August 2013,
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Daryl F Venable, and
Anna L Blobaum, and
Frank W Byers, and
Analisa Thompson Gray, and
J Scott Daniels, and
Colleen M Niswender, and
Carrie K Jones, and
P Jeffrey Conn, and
Craig W Lindsley, and
Kyle A Emmitte
September 2021,
ACS omega,
Andrew S Felts, and
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Katrina A Bollinger, and
Daryl F Venable, and
Anna L Blobaum, and
Frank W Byers, and
Analisa Thompson Gray, and
J Scott Daniels, and
Colleen M Niswender, and
Carrie K Jones, and
P Jeffrey Conn, and
Craig W Lindsley, and
Kyle A Emmitte
October 2022,
ACS chemical biology,
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Anna L Blobaum, and
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Analisa Thompson Gray, and
J Scott Daniels, and
Colleen M Niswender, and
Carrie K Jones, and
P Jeffrey Conn, and
Craig W Lindsley, and
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January 2004,
Bioorganic & medicinal chemistry,
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Alice L Rodriguez, and
Ryan D Morrison, and
Katrina A Bollinger, and
Daryl F Venable, and
Anna L Blobaum, and
Frank W Byers, and
Analisa Thompson Gray, and
J Scott Daniels, and
Colleen M Niswender, and
Carrie K Jones, and
P Jeffrey Conn, and
Craig W Lindsley, and
Kyle A Emmitte
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