Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead

Bioorg Med Chem Lett. 2009 Feb 1;19(3):962-6. doi: 10.1016/j.bmcl.2008.11.104. Epub 2008 Dec 25.

Abstract

This Letter describes the synthesis and SAR of two mGluR4 positive allosteric modulator leads, 6 and 7. VU001171 (6) represents the most potent (EC(50)=650 nM), efficacious (141% Glu Max) and largest fold shift (36-fold) of any mGluR4 PAM reported to date. However, this work highlights the challenges in hit-to-lead for mGluR4 PAMs, with multiple confirmed HTS hits displaying little or no tractable SAR.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Animals
  • CHO Cells
  • Chemistry, Pharmaceutical / methods*
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Evaluation, Preclinical
  • Models, Chemical
  • Molecular Conformation
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship

Substances

  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 4