Synthesis and activity of 4,5-diarylimidazoles as human CB1 receptor inverse agonists

The synthesis and structure–activity relationships for a series of substituted 4,5-diphenylimidazole-2-carboxamide derivatives 2b as selective, orally active human CB1 inverse agonists are described. Structure–activity relationship studies directed toward the optimization of 4,5-diarylimidazole-2-ca...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2005-03, Vol.15 (5), p.1441-1446
Main Authors: Plummer, Christopher W., Finke, Paul E., Mills, Sander G., Wang, Junying, Tong, Xinchun, Doss, George A., Fong, Tung M., Lao, Julie Z., Schaeffer, Marie-Therese, Chen, Jing, Shen, Chun-Pyn, Stribling, D. Sloan, Shearman, Lauren P., Strack, Alison M., Van der Ploeg, Lex H.T.
Format: Article
Language:English
Subjects:
Animals
Area Under Curve
Binding, Competitive - drug effects
Biological and medical sciences
Body Weight - drug effects
Cannabinoid
CB1 inverse agonist
Disease Models, Animal
Drug Evaluation, Preclinical
Eating - drug effects
General and cellular metabolism. Vitamins
Humans
Imidazole
Imidazoles - chemical synthesis
Imidazoles - pharmacokinetics
Imidazoles - pharmacology
Medical sciences
Miscellaneous
Molecular Structure
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Obesity
Obesity - drug therapy
Pharmacology. Drug treatments
Rats
Receptor, Cannabinoid, CB1 - drug effects
Structure-Activity Relationship
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Summary:The synthesis and structure–activity relationships for a series of substituted 4,5-diphenylimidazole-2-carboxamide derivatives 2b as selective, orally active human CB1 inverse agonists are described. Structure–activity relationship studies directed toward the optimization of 4,5-diarylimidazole-2-carboxamide analogs as human CB1 receptor inverse agonists resulted in the discovery of the two amide derivatives 24a and b (hCB1 IC 50 = 6.1 and 4.0 nM) which also demonstrated efficacy in overnight feeding studies in the rat for reduction in both food intake and overall body weight.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.12.078