Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety

Bioorg Med Chem. 2019 Aug 1;27(15):3440-3450. doi: 10.1016/j.bmc.2019.06.021. Epub 2019 Jun 19.

Abstract

We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

Keywords: Conditioned avoidance response (CAR); Phosphodiesterase (PDE) 10A; Pyrazolopyrimidine; Quinoxaline; Schizophrenia.

MeSH terms

  • Animals
  • Cattle
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / metabolism*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Stilbenes / chemistry
  • Stilbenes / pharmacology*
  • Structure-Activity Relationship

Substances

  • Phosphodiesterase Inhibitors
  • Pyrimidines
  • Stilbenes
  • Phosphoric Diester Hydrolases