Design, optimization, and in vivo evaluation of a series of pyridine derivatives with dual NK1 antagonism and SERT inhibition for the treatment of depression

Bioorg Med Chem Lett. 2013 Jan 15;23(2):407-11. doi: 10.1016/j.bmcl.2012.11.094. Epub 2012 Nov 30.

Abstract

A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.

MeSH terms

  • Animals
  • Depression / drug therapy*
  • Disease Models, Animal
  • Drug Design*
  • Gerbillinae
  • Inhibitory Concentration 50
  • Molecular Structure
  • Neurokinin-1 Receptor Antagonists*
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / therapeutic use
  • Serotonin Antagonists* / chemical synthesis
  • Serotonin Antagonists* / chemistry
  • Serotonin Antagonists* / therapeutic use

Substances

  • Neurokinin-1 Receptor Antagonists
  • Pyridines
  • Serotonin Antagonists