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

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1679-1685. doi: 10.1016/j.bmcl.2018.04.053. Epub 2018 Apr 22.

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(5)); Negative allosteric modulator (NAM); Quinoline.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Male
  • Molecular Structure
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Structure-Activity Relationship

Substances

  • 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide
  • Pyrimidines
  • Quinolines
  • Receptor, Metabotropic Glutamate 5