Design, synthesis and bioevalucation of novel 2,3-dihydro-1H-inden-1-amine derivatives as potent and selective human monoamine oxidase B inhibitors based on rasagiline

Eur J Med Chem. 2018 Feb 10:145:588-593. doi: 10.1016/j.ejmech.2018.01.029. Epub 2018 Jan 10.

Abstract

Parkinson's disease (PD) is associated with elevated levels of hMAO-B in the brain, and MAO-B has been recognized a successful target for developing anti-PD drugs. Herein we report rasagiline derivatives as novel potent and selective hMAO-B inhibitors. They were designed by employing fragment-based drug design strategy to link rasagiline and hydrophobic fragments, which may target a hydrophobic pocket in the entrance cavity of hMAO-B. Different linkers such as -OCH2-, -SCH2-, -OCH2CH2-, -OCH2CH2O-, -OCH2CH2CH2O- were tried. A promising selective hMAO-B inhibitor D14 with similar inhibitory activity as rasagiline and improved isoform selectivity was yielded. The selectivity profile of compounds reported herein suggests that we can further develop more potent hMAO-B inhibitors with high isoform selectivity through this strategy.

Keywords: Fragment-based drug design; Isoform selectivity; Structure activity relationship; hMAO-B.

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Indans / chemistry
  • Indans / pharmacology*
  • Indenes / chemical synthesis
  • Indenes / chemistry
  • Indenes / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Amines
  • Indans
  • Indenes
  • Monoamine Oxidase Inhibitors
  • rasagiline
  • Monoamine Oxidase