Dual neurokinin NK(1)/NK(2) antagonists: N-[(R,R)-(E)-1-arylmethyl-3-(2-oxo-azepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamides and 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-arylmethyl-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamides

Bioorg Med Chem Lett. 2001 Dec 3;11(23):3081-4. doi: 10.1016/s0960-894x(01)00631-x.

Abstract

Based on the structure of N-[(R,R)-(E)-1-(4-chlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1), attempts to improve the NK(2) affinity have resulted in the discovery of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (9, DNK333) exhibiting a 5-fold improved affinity to the NK(2) receptor in comparison to 1. Simplification of the structure via elimination of a chiral centre led to 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamide (22), a potent and fairly balanced NK(1)/NK(2) antagonist.

MeSH terms

  • Animals
  • Aza Compounds / chemistry*
  • Aza Compounds / pharmacology*
  • Benzamides / chemistry*
  • Benzamides / pharmacology*
  • CHO Cells
  • Cricetinae
  • Drug Evaluation, Preclinical
  • Humans
  • Hydrazines / pharmacology*
  • Inhibitory Concentration 50
  • Neurokinin-1 Receptor Antagonists*
  • Receptors, Neurokinin-1 / metabolism
  • Receptors, Neurokinin-2 / antagonists & inhibitors*
  • Receptors, Neurokinin-2 / metabolism
  • Structure-Activity Relationship

Substances

  • 3-(N'-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N'-methylhydrazino)-N-(-2-oxo-azepan-3-yl)propionamide
  • Aza Compounds
  • Benzamides
  • DNK 333
  • Hydrazines
  • N-(1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl)-N-methyl-3,5,-bis-trifluoromethyl-benzamide
  • Neurokinin-1 Receptor Antagonists
  • Receptors, Neurokinin-1
  • Receptors, Neurokinin-2