Novel PDE5 inhibitors derived from rutaecarpine for the treatment of Alzheimer's disease

Bioorg Med Chem Lett. 2020 May 1;30(9):127097. doi: 10.1016/j.bmcl.2020.127097. Epub 2020 Mar 7.

Abstract

A series of novel rutaecarpine derivatives were synthesized and subjected to pharmacological evaluation as PDE5 inhibitors. The structure-activity relationships were discussed and their binding conformation and simultaneous interaction mode were further clarified by the molecular docking studies. Among the 25 analogues, compound 8i exhibited most potent PDE5 inhibition with IC50 values about 0.086 μM. Moreover, it also produced good effects against scopolamine-induced cognitive impairment in vivo. These results might bring significant instruction for further development of potential PDE5 inhibitors derived from rutaecarpine as a good candidate drug for the treatment of Alzheimer's disease.

Keywords: Alzheimer’s disease; PDE5 inhibitors; Rutaecarpine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Animals
  • Cholinergic Antagonists / toxicity
  • Cognitive Dysfunction / chemically induced*
  • Cognitive Dysfunction / drug therapy
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
  • Dose-Response Relationship, Drug
  • Indole Alkaloids / chemistry*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Morris Water Maze Test
  • Phosphodiesterase 5 Inhibitors / administration & dosage
  • Phosphodiesterase 5 Inhibitors / chemical synthesis*
  • Phosphodiesterase 5 Inhibitors / chemistry
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Protein Conformation
  • Quinazolines / chemistry*
  • Scopolamine / toxicity

Substances

  • Cholinergic Antagonists
  • Indole Alkaloids
  • Phosphodiesterase 5 Inhibitors
  • Quinazolines
  • rutecarpine
  • Scopolamine
  • Cyclic Nucleotide Phosphodiesterases, Type 5