Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

Andrew S. Felts, Alice L. Rodriguez, Ryan D. Morrison, Anna L. Blobaum, Frank W. Byers, J. Scott Daniels, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley, Kyle A. Emmitte

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1 Scopus citations

Abstract

Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu5 NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu5 assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.

Original languageEnglish
Pages (from-to)1679-1685
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number10
DOIs
StatePublished - 1 Jun 2018

Keywords

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

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    Felts, A. S., Rodriguez, A. L., Morrison, R. D., Blobaum, A. L., Byers, F. W., Daniels, J. S., Niswender, C. M., Conn, P. J., Lindsley, C. W., & Emmitte, K. A. (2018). Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. Bioorganic and Medicinal Chemistry Letters, 28(10), 1679-1685. https://doi.org/10.1016/j.bmcl.2018.04.053