Discovery of novel substituted octahydropyrrolo[3,4-c]pyrroles as dual orexin receptor antagonists for insomnia treatment

Bioorg Med Chem Lett. 2017 Mar 15;27(6):1458-1462. doi: 10.1016/j.bmcl.2017.01.075. Epub 2017 Jan 28.

Abstract

A series of octahydropyrrolo[3,4-c]pyrroles were synthesized and evaluated by orexin 1 and 2 receptor (OX1 & 2 R) antagonists assays. Compound 14l with potent OXR antagonist activity and suitable pharmacokinetic behavior was chosen to be investigated in an EEG study, which demonstrated effects of sleep promotion comparable to Suvorexant. Furthermore, the di-fluro substituted analogs exhibited reduced hERG inhibition while maintaining moderate potency.

Keywords: Antagonists; Insomnia; Octahydropyrrolo[3,4-c]pyrroles; Orexin receptors.

MeSH terms

  • Animals
  • Drug Discovery
  • Electroencephalography
  • Humans
  • Male
  • Orexin Receptor Antagonists / chemistry*
  • Orexin Receptor Antagonists / pharmacology*
  • Orexin Receptor Antagonists / therapeutic use
  • Pyrroles / chemistry*
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Pyrroles / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Sleep Initiation and Maintenance Disorders / drug therapy*
  • Sleep Initiation and Maintenance Disorders / physiopathology
  • Structure-Activity Relationship

Substances

  • Orexin Receptor Antagonists
  • Pyrroles