Novel tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one: Design, synthesis, model and use as hMAO-B inhibitors

Bioorg Med Chem. 2016 Apr 15;24(8):1741-8. doi: 10.1016/j.bmc.2016.02.045. Epub 2016 Mar 3.

Abstract

Based on our recently reported selective hMAO-A inhibitors, on which, the intramolecular cyclization led to a very interesting change of isoform selectivity. A series of selective hMAO-B inhibitors (3a-3u) with novel scaffold of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one were designed and synthesized. Compound 3u (IC50=221 nM) exhibited the best inhibitory activity and isoform selectivity against hMAO-B, superior to selegiline (IC50=321 nM), which is a commercial selective hMAO-B inhibitor used to Parkinson's disease. Modeling study indicated that the selectivity of our compounds to hMAO-B is determined by at least two residues, i.e., Ile 199 and Cys 172 (or corresponded Phe 208 and Asn 181 of hMAO-A). These data support further studies to assess rational design of more efficiently selective hMAO-B inhibitors.

Keywords: Anti-Parkinson; Benzoxazepinone; Isoform selectivity; Selective hMAO-B inhibitor; hMAO.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoxazines / chemical synthesis
  • Benzoxazines / chemistry
  • Benzoxazines / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzoxazines
  • Monoamine Oxidase Inhibitors
  • Pyrazoles
  • pyrazolo(1,5-d)(1,4)benzoxazepin-5(6H)-one
  • Monoamine Oxidase