Design and synthesis of a novel 2-oxindole scaffold as a highly potent and brain-penetrant phosphodiesterase 10A inhibitor

Bioorg Med Chem. 2015 Nov 15;23(22):7138-49. doi: 10.1016/j.bmc.2015.10.002. Epub 2015 Oct 9.

Abstract

Highly potent and brain-penetrant phosphodiesterase 10A (PDE10A) inhibitors based on the 2-oxindole scaffold were designed and synthesized. (2-Oxo-1,3-oxazolidin-3-yl)phenyl derivative 1 showed the high P-glycoprotein (P-gp) efflux (efflux ratio (ER)=6.2) despite the potent PDE10A inhibitory activity (IC50=0.94 nM). We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity by utilizing structure-based drug design (SBDD) techniques based on the X-ray crystal structure with PDE10A. Finally, 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (19e) was identified with improved P-gp efflux (ER=1.4) and an excellent PDE10A inhibitory activity (IC50=0.080 nM). Compound 19e also exhibited satisfactory brain penetration, and suppressed PCP-induced hyperlocomotion with a minimum effective dose of 0.3mg/kg by oral administration in mice.

Keywords: Inhibitors; P-gp-mediated efflux; Phosphodiesterase 10A (PDE10A); Schizophrenia.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Brain / metabolism*
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Activation / drug effects
  • Half-Life
  • Indoles / chemical synthesis*
  • Indoles / chemistry*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Mice
  • Molecular Conformation
  • Molecular Docking Simulation
  • Motor Activity / drug effects
  • Oxindoles
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoric Diester Hydrolases / chemistry*
  • Phosphoric Diester Hydrolases / metabolism
  • Pyridazines / chemical synthesis*
  • Pyridazines / chemistry
  • Pyridazines / pharmacokinetics
  • Pyridazines / pharmacology*

Substances

  • 1-(cyclopropylmethyl)-4-fluoro-5-(5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one
  • Indoles
  • Oxindoles
  • Phosphodiesterase Inhibitors
  • Pyridazines
  • 2-oxindole
  • Pde10a protein, mouse
  • Phosphoric Diester Hydrolases