Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species

Bioorg Med Chem Lett. 2018 Apr 1;28(6):1122-1126. doi: 10.1016/j.bmcl.2018.01.039. Epub 2018 Feb 10.

Abstract

An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.

Keywords: Cognition; Optimization; PDE2; Phosphodiesterase inhibitor; Schizophrenia.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetic Acid / chemical synthesis
  • Acetic Acid / chemistry
  • Acetic Acid / pharmacology*
  • Animals
  • Catalytic Domain / drug effects
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / antagonists & inhibitors*
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / metabolism
  • Dose-Response Relationship, Drug
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Phosphodiesterase Inhibitors / chemical synthesis
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Indoles
  • Phosphodiesterase Inhibitors
  • indole
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Acetic Acid