Acyl dihydropyrazolo[1,5-a]pyrimidinones as metabotropic glutamate receptor 5 positive allosteric modulators

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5115-20. doi: 10.1016/j.bmcl.2015.10.009. Epub 2015 Oct 9.

Abstract

We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1,5-a]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5,6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described.

Keywords: Metabotropic glutamate receptor 5 (mGlu(5)); Positive allosteric modulator (PAM).

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Animals
  • Brain / metabolism*
  • Dogs
  • Humans
  • Ligands
  • Male
  • Motor Activity / drug effects
  • Pyrazoles / blood
  • Pyrazoles / chemical synthesis
  • Pyrazoles / isolation & purification
  • Pyrazoles / pharmacokinetics*
  • Pyrazoles / pharmacology
  • Pyrimidines / blood
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / pharmacology
  • Pyrimidinones / blood
  • Pyrimidinones / chemical synthesis
  • Pyrimidinones / isolation & purification
  • Pyrimidinones / pharmacokinetics*
  • Pyrimidinones / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Metabotropic Glutamate 5 / agonists*
  • Structure-Activity Relationship

Substances

  • 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo(1,5-a)pyrimidin-4(5H)-yl)ethanone
  • Ligands
  • Pyrazoles
  • Pyrimidines
  • Pyrimidinones
  • Receptor, Metabotropic Glutamate 5