Discovery of a novel 2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione series promoting neurogenesis of human neural progenitor cells

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3748-53. doi: 10.1016/j.bmcl.2015.05.084. Epub 2015 Jun 11.

Abstract

A novel neurogenic compound (1), discovered from a mouse neural progenitor cell (NPC) screen, showed profound neurogenic effect on human NPCs. Synthesis and SAR of this novel 2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione series are described. Compound 20 is brain penetrable in rodents, and promotes neurogenesis in wild type mice, therefore it is a good tool molecule to study neurogenesis induction as a potential treatment for conditions associated with neurogenesis impairment diseases.

Keywords: Neural progenitor cell; Neurogenesis; Structure–activity relationship.

MeSH terms

  • Administration, Oral
  • Animals
  • Brain / drug effects
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Chemistry Techniques, Synthetic
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Evaluation, Preclinical / methods
  • Half-Life
  • Humans
  • Isoquinolines / administration & dosage
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacokinetics
  • Isoquinolines / pharmacology
  • Mice, Inbred C57BL
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects*
  • Neurogenesis / drug effects*
  • Pyrazines / administration & dosage
  • Pyrazines / chemistry
  • Pyrazines / pharmacokinetics*
  • Structure-Activity Relationship*

Substances

  • 2,3,11,11a-tetrahydro-1H-pyrazino(1,2-b)isoquinoline-1,4(6H)-dione
  • Isoquinolines
  • Pyrazines