Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu(2)/mGlu(3) NAMs

Bioorg Med Chem Lett. 2014 Jun 15;24(12):2693-8. doi: 10.1016/j.bmcl.2014.04.051. Epub 2014 Apr 20.

Abstract

Herein we report the design and synthesis of a series of substituted pyrazolo[1,5-a]quinazolin-5(4H)-ones as negative allosteric modulators of metabotropic glutamate receptors 2 and 3 (mGlu2 and mGlu3, respectively). Development of this series was initiated by reports that pyrazolo[1,5-a]quinazoline-derived scaffolds can yield compounds with activity at group II mGlu receptors which are prone to molecular switching following small structural changes. Several potent analogues, including 4-methyl-2-phenyl-8-(pyrimidin-5-yl)pyrazolo[1,5-a]quinazolin-5(4H)-one (10b), were discovered with potent in vitro activity as dual mGlu2/mGlu3 NAMs, with excellent selectivity versus the other mGluRs.

Keywords: Metabotropic glutamate receptor 2; Metabotropic glutamate receptor 3; Negative allosteric modulator (NAM); mGlu(2) receptor; mGlu(3) receptor.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Drug Design
  • Inhibitory Concentration 50
  • Molecular Structure
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Receptors, Metabotropic Glutamate / chemistry
  • Receptors, Metabotropic Glutamate / drug effects*
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship

Substances

  • Pyrazoles
  • Quinazolines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor 3