Design, synthesis, and structure-activity relationships of novel bicyclic azole-amines as negative allosteric modulators of metabotropic glutamate receptor 5

J Med Chem. 2010 Oct 14;53(19):7107-18. doi: 10.1021/jm100736h.

Abstract

A novel series of diaryl bicyclic azole-amines that are potent selective negative modulators of metabotropic glutamate receptor 5 (mGluR5) were identified through rational design. An initial hit compound 5a of modest potency (IC(50) = 1.2 μM) was synthesized. Evaluation of structure-activity relationships (SAR) on the left-hand side of the molecule revealed a preference for a 2-substituted pyridine group linked directly to the central heterocycle. Variation of the central azolo-amine portion of the molecule revealed a preference for the [4,5-c]-oxazoloazepine scaffold, while right-hand side variants showed a preference for ortho- and meta-substituted benzene rings linked directly to the tertiary amine of the saturated heterocycle. These iterations led to the synthesis of 29b, a potent (IC(50) = 16 nM) and selective negative modulator that showed good brain penetrance, high receptor occupancy, and a duration of action greater than 1 h in rat when administered intraperitoneally. Formal PK studies in rat and Rhesus monkey revealed a short half-life that was attributable to high first-pass clearance.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Azepines / chemical synthesis*
  • Azepines / pharmacokinetics
  • Azepines / pharmacology
  • Blood-Brain Barrier / metabolism
  • Drug Design
  • Excitatory Amino Acid Agents / chemical synthesis*
  • Excitatory Amino Acid Agents / pharmacokinetics
  • Excitatory Amino Acid Agents / pharmacology
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / pharmacokinetics
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Macaca mulatta
  • Nitriles / chemical synthesis*
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology
  • Oxazoles / chemical synthesis*
  • Oxazoles / pharmacokinetics
  • Oxazoles / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship

Substances

  • 3-fluoro-5-(2-(pyridin-2-yl)-7,8-dihydro-4H-oxazolo(4,5-c)azepin-5(6H)-yl)benzonitrile
  • Azepines
  • Excitatory Amino Acid Agents
  • Grm5 protein, rat
  • Heterocyclic Compounds, 2-Ring
  • Nitriles
  • Oxazoles
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate