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

Andrew S. Felts, Alice L. Rodriguez, Ryan D. Morrison, Katrina A. Bollinger, Daryl F. Venable, Anna L. Blobaum, Frank W. Byers, Analisa Thompson Gray, J. Scott Daniels, Colleen M. Niswender, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte

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Abstract

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.

Original languageEnglish
Pages (from-to)4858-4866
Number of pages9
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number21
DOIs
StatePublished - 1 Nov 2017

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Keywords

  • Central nervous system (CNS)
  • G-protein coupled receptor (GPCR)
  • Heterocycle
  • Metabotropic glutamate receptor subtype 5 (mGlu)
  • Negative allosteric modulator (NAM)

Cite this

Felts, A. S., Rodriguez, A. L., Morrison, R. D., Bollinger, K. A., Venable, D. F., Blobaum, A. L., Byers, F. W., Thompson Gray, A., Daniels, J. S., Niswender, C. M., Jones, C. K., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2017). 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. Bioorganic and Medicinal Chemistry Letters, 27(21), 4858-4866. https://doi.org/10.1016/j.bmcl.2017.09.042