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

A series of 3-aryl-5-acylpiperazinyl-pyrazoles (e.g., 3a–b) initially identified through a high-throughput screening campaign using the aequorin Ca²⁺ bioluminescence assay as novel, potent small molecule antagonists of the G protein-coupled human tachykinin NK₃ receptor (hNK3-R) is described. Prelim...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-04, Vol.21 (7), p.1991-1996
Main Authors: Hoveyda, Hamid R, Roy, Marie-Odile, Blanc, Sebastien, Noël, Sophie, Salvino, Joseph M, Ator, Mark A, Fraser, Graeme
Format: Article
Language:English
Subjects:
aequorin
Animals
antagonists
Biological and medical sciences
bioluminescence
brain
calcium
Cell Line, Tumor
cytotoxicity
Drug Discovery
Drug Screening Assays, Antitumor
Humans
Inhibitory Concentration 50
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
permeability
pharmacokinetics
Pharmacology. Drug treatments
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Pyrazoles - chemistry
Pyrazoles - pharmacokinetics
Pyrazoles - pharmacology
Rats
receptors
Receptors, Neurokinin-3 - antagonists & inhibitors
rodents
screening
Structure-Activity Relationship
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Summary:A series of 3-aryl-5-acylpiperazinyl-pyrazoles (e.g., 3a–b) initially identified through a high-throughput screening campaign using the aequorin Ca²⁺ bioluminescence assay as novel, potent small molecule antagonists of the G protein-coupled human tachykinin NK₃ 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.02.033