Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A

Bioorg Med Chem Lett. 2015 May 1;25(9):1864-8. doi: 10.1016/j.bmcl.2015.03.050. Epub 2015 Mar 26.

Abstract

The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.

Keywords: PCP-induced hyperlocomotion; PDE10A; PDE10A inhibitor; Phosphodiesterase inhibitor; Schizophrenia.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Locomotion / drug effects
  • Models, Molecular
  • Molecular Structure
  • Phencyclidine
  • Phosphoric Diester Hydrolases / metabolism*
  • Rats
  • Structure-Activity Relationship
  • Triazoles / administration & dosage
  • Triazoles / chemical synthesis
  • Triazoles / pharmacology*

Substances

  • Triazoles
  • PDE10A protein, human
  • Phosphoric Diester Hydrolases
  • Phencyclidine

Associated data

  • PDB/47QH
  • PDB/4YS7