2-Aryl indole NK(1) antagonists: optimisation of the amide substituent

Bioorg Med Chem Lett. 2001 Dec 3;11(23):3031-4. doi: 10.1016/s0960-894x(01)00616-3.

Abstract

The in vivo properties of a series of 2-arylindole NK(1) antagonists have been improved, by modification of the amide substituent. The 1-(2-methoxyphenyl)piperazine amide was identified as a major area of metabolism in the lead compound 1. Replacement of this amine moiety by a 4-benzyl-4-hydroxypiperidine resulted in a compound 18 with reduced clearance and improved central duration of action.

MeSH terms

  • Administration, Oral
  • Amides / chemistry*
  • Animals
  • Biological Availability
  • Cricetinae
  • Drug Evaluation, Preclinical
  • Indoles / pharmacokinetics*
  • Inhibitory Concentration 50
  • Metabolic Clearance Rate
  • Neurokinin A / antagonists & inhibitors*
  • Piperazines / chemistry
  • Rats
  • Structure-Activity Relationship

Substances

  • 1-(2-methoxyphenyl)piperazine amide
  • Amides
  • Indoles
  • Piperazines
  • Neurokinin A