Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors

Bioorg Med Chem Lett. 2016 Sep 1;26(17):4216-22. doi: 10.1016/j.bmcl.2016.07.054. Epub 2016 Jul 25.

Abstract

Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.

Keywords: Brain penetration; GPCR; GSIS; Insulin secretagogues; PDE10a inhibitor; Type 2 diabetes.

MeSH terms

  • Animals
  • Binding Sites
  • Drug Design*
  • Glucose Tolerance Test
  • Half-Life
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacokinetics
  • Insulin / metabolism
  • Molecular Docking Simulation
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Phosphoric Diester Hydrolases / chemistry*
  • Phosphoric Diester Hydrolases / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Insulin
  • Phosphodiesterase Inhibitors
  • Pyridines
  • imidazopyridine
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases