Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu1

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5091-6. doi: 10.1016/j.bmcl.2013.07.029. Epub 2013 Jul 23.

Abstract

Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds.

Keywords: Allosteric modulator; CNS; GPCR; Glutamate; Octahydropyrrolo[3,4-c]pyrrole; mGlu(1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Rats
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Pyrroles
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • octahydropyrrolo(3,4-c)pyrrole
  • Cytochrome P-450 Enzyme System