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 Allen Emmitte

Research output: Contribution to journalArticleResearchpeer-review

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

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Metabotropic Glutamate 5 Receptor
Metabotropic Glutamate Receptors
Modulators
Assays
Metabolism
Ether
Rats
Carbon
Oxygen
Derivatives
Atoms
Liver
quinoline

Keywords

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

Cite this

Felts, Andrew S. ; Rodriguez, Alice L. ; Morrison, Ryan D. ; Blobaum, Anna L. ; Byers, Frank W. ; Daniels, J. Scott ; Niswender, Colleen M. ; Conn, P. Jeffrey ; Lindsley, Craig W. ; Emmitte, Kyle Allen. / Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. In: Bioorganic and Medicinal Chemistry Letters. 2018 ; Vol. 28, No. 10. pp. 1679-1685.
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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.",
keywords = "Central nervous system (CNS), G protein-coupled receptor (GPCR), Metabotropic glutamate receptor subtype 5 (mGlu), Negative allosteric modulator (NAM), Quinoline",
author = "Felts, {Andrew S.} and Rodriguez, {Alice L.} and Morrison, {Ryan D.} and Blobaum, {Anna L.} and Byers, {Frank W.} and Daniels, {J. Scott} and Niswender, {Colleen M.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.} and Emmitte, {Kyle Allen}",
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Felts, AS, Rodriguez, AL, Morrison, RD, Blobaum, AL, Byers, FW, Daniels, JS, Niswender, CM, Conn, PJ, Lindsley, CW & Emmitte, KA 2018, 'Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 10, pp. 1679-1685. https://doi.org/10.1016/j.bmcl.2018.04.053

Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. / Felts, Andrew S.; Rodriguez, Alice L.; Morrison, Ryan D.; Blobaum, Anna L.; Byers, Frank W.; Daniels, J. Scott; Niswender, Colleen M.; Conn, P. Jeffrey; Lindsley, Craig W.; Emmitte, Kyle Allen.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 28, No. 10, 01.06.2018, p. 1679-1685.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Daniels, J. Scott

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AU - Emmitte, Kyle Allen

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