Synthesis, Cannabinoid Receptor Affinity, and Molecular Modeling Studies of Substituted 1-Aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides

• Published in: Journal of medicinal chemistry 2008-03, Vol.51 (6), p.1560-1576
• Main Authors: Silvestri, Romano, Cascio, Maria Grazia, La Regina, Giuseppe, Piscitelli, Francesco, Lavecchia, Antonio, Brizzi, Antonella, Pasquini, Serena, Botta, Maurizio, Novellino, Ettore, Di Marzo, Vincenzo, Corelli, Federico
• Format: Article
• Language: English
• Subjects: Binding, Competitive; Computer Simulation; Humans; Hydrogen Bonding; Ligands; Models, Molecular; Molecular Structure; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Receptor, Cannabinoid, CB1 - drug effects; Receptor, Cannabinoid, CB2 - drug effects; Recombinant Proteins - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070566z

The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB1 and hCB2 receptor affinity. Compounds bearing 2,4-dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB1. On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB1 receptor (K i (CB2)/K i (CB1) = 140.7). Derivative 30, the most potent hCB1 ligand (K i = 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC50 ∼1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptorsʼ inactive state and the inverse agonist activity.