Discovery of 3-aryl-5-acylpiperazinyl-pyrazoles as antagonists to the NK3 receptor

Bioorg Med Chem Lett. 2011 Apr 1;21(7):1991-6. doi: 10.1016/j.bmcl.2011.02.033. Epub 2011 Feb 13.


A series of 3-aryl-5-acylpiperazinyl-pyrazoles (e.g., 3a-b) initially identified through a high-throughput screening campaign using the aequorin Ca(2+) bioluminescence assay as novel, potent small molecule antagonists of the G protein-coupled human tachykinin NK(3) receptor (hNK3-R) is described. Preliminary profiling revealed poor plasma and metabolic stability for these structures in rodents. Further optimization efforts resulted in analogs with improved potency, stability, and pharmacokinetic properties as well as good brain permeability, for example, compounds 26 and 42. Unexpected cytotoxicity was observed in such N-Me pyrazole structures as compounds 41-42.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Discovery
  • Drug Screening Assays, Antitumor
  • Humans
  • Inhibitory Concentration 50
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Rats
  • Receptors, Neurokinin-3 / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Pyrazoles
  • Receptors, Neurokinin-3