2-Substituted piperazine-derived imidazole carboxamides as potent and selective CCK1R agonists for the treatment of obesity

The synthesis and biological profile of imidazole carboxamides of general structure 6 as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. The discovery and structure–activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as poten...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-09, Vol.18 (17), p.4833-4837
Main Authors: Berger, Richard, Zhu, Cheng, Hansen, Alexa R., Harper, Bart, Chen, Zhesheng, Holt, Tom G., Hubert, James, Lee, Susan J., Pan, Jie, Qian, Su, Reitman, Marc L., Strack, Alison M., Weingarth, Drew T., Wolff, Michael, MacNeil, Douglas J., Weber, Ann E., Edmondson, Scott D.
Format: Article
Language:English
Subjects:
Animals
Anti-Obesity Agents - chemical synthesis
Anti-Obesity Agents - chemistry
Anti-Obesity Agents - pharmacology
Benzodiazepines - chemical synthesis
Benzodiazepines - chemistry
Benzodiazepines - pharmacology
Biological and medical sciences
CCK1R
Chemokines, CC
Cholecystokinin
General and cellular metabolism. Vitamins
Humans
Imidazole carboxamides
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Medical sciences
Methylamines - chemical synthesis
Methylamines - chemistry
Methylamines - pharmacology
Mice
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Obesity
Obesity - drug therapy
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Piperazines - chemistry
Receptor, Cholecystokinin A - agonists
Receptors, Cholecystokinin - agonists
Receptors, Cholecystokinin - chemistry
Thiazoles - chemical synthesis
Thiazoles - chemistry
Thiazoles - pharmacology
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Description
Summary:The synthesis and biological profile of imidazole carboxamides of general structure 6 as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. The discovery and structure–activity relationship of 1,2-diarylimidazole piperazine carboxamides bearing polar side chains as potent and selective cholecystokinin 1 receptor (CCK1R) agonists are described. Optimization of this series resulted in the discovery of isopropyl carboxamide 40, a CCK1R agonist with sub-nanomolar functional and binding activity as well as excellent potency in a mouse overnight food intake reduction assay.
ISSN:0960-894X
0968-0896
1464-3405
1464-3391
DOI:10.1016/j.bmcl.2008.07.083