Rational design, synthesis and biological evaluation of new 1,5-diarylpyrazole derivatives as CB1 receptor antagonists, structurally related to rimonabant

Among cannabinoid type-1 (CB(1)) receptor antagonists, those developed around the 1,5-diarylpyrazole scaffold of rimonabant (Acomplia are the most extensively investigated. In recent years, many SAR and QSAR reports on this topic have been published, focusing on the substitution and orientation of t...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2008-12, Vol.43 (12), p.2627-2638
Main Authors: MENOZZI, Giulia, FOSSA, Paola, CICHERO, Elena, SPALLAROSSA, Andrea, RANISE, Angelo, MOSTI, Luisa
Format: Article
Language:English
Subjects:
Binding, Competitive
Biological and medical sciences
Drug Design
Humans
Hydrogen Bonding
Ligands
Medical sciences
Miscellaneous
Models, Molecular
Molecular Structure
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Piperidines - chemistry
Pyrazoles - chemistry
Pyrazoles - pharmacology
Receptor, Cannabinoid, CB1 - antagonists & inhibitors
Receptor, Cannabinoid, CB2 - antagonists & inhibitors
Stereoisomerism
Structure-Activity Relationship
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Summary:Among cannabinoid type-1 (CB(1)) receptor antagonists, those developed around the 1,5-diarylpyrazole scaffold of rimonabant (Acomplia are the most extensively investigated. In recent years, many SAR and QSAR reports on this topic have been published, focusing on the substitution and orientation of the N1 and C5 aryl functionalities and on the substituents at the 3-carboxamide position. In this context, the purpose of our study was to design and synthesize a set of 1-(2,4-dichlorophenyl)-5-arylpyrazoles strictly related to rimonabant, but with the hydrazide/amide group shifted from position 3 to position 4 of the pyrazole scaffold. The synthesized compounds were evaluated in vitro for their affinity on human CB(1) and CB(2) (cannabinoid type-2) receptors. Computational studies, performed both in the design step and after biological assays, contributed to rationalize the obtained results in terms of specific molecular interactions between antagonists and the human CB(1) receptor.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2008.01.043