Diaryl Dihydropyrazole-3-carboxamides with Significant In Vivo Antiobesity Activity Related to CB1 Receptor Antagonism: Synthesis, Biological Evaluation, and Molecular Modeling in the Homology Model

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• 作者：Brijesh Kumar Srivastava ; Amit Joharapurkar ; Saurin Raval ; Jayendra Z. Patel ; Rina Soni ; Preeti Raval ; Archana Gite ; Amitgiri Goswami ; Nisha Sadhwani ; Neha Gandhi ; Harilal Patel ; Bhupendra Mishra ; Man
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：5951 - 5966
• 全文大小：331K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activitieswere evaluated for appetite suppression and body weight reduction in animal models. Depending on thechemical modification of the selected dihydropyrazole scaffold, the lead compounds-the bisulfate salt of(±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30-showed significant body weight reduction in vivo, which isattributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecularmodeling studies also showed interactions of two isomers of (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology modelsimilar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide(rimonabant) 1 and 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.