Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM)

J Med Chem. 2013 Jun 27;56(12):5208-12. doi: 10.1021/jm400439t. Epub 2013 Jun 13.

Abstract

A multidimensional, iterative parallel synthesis effort identified a series of highly selective mGlu3 NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Drug Discovery*
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Piperidines / chemistry
  • Piperidines / metabolism*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Rats
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / metabolism*
  • Substrate Specificity

Substances

  • (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl)(3-hydroxypiperidin-1-yl)methanone
  • Piperidines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 3