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

Srivastava, Brijesh Kumar, Joharapurkar, Amit, Raval, Saurin, Patel, Jayendra Z., Soni, Rina, Raval, Preeti, Gite, Archana, Goswami, Amitgiri, Sadhwani, Nisha, Gandhi, Neha, Patel, Harilal, Mishra, Bhupendra, Solanki, Manish, Pandey, Bipin, Jain, Mukul R., & Patel, Pankaj R. (2007) 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. Journal of Medicinal Chemistry, 50(24), pp. 5951-5966.

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Abstract

A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compoundsthe 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 30showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling 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 model similar 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.

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ID Code: 93842
Item Type: Journal Article
Refereed: Yes
DOI: 10.1021/jm061490u
ISSN: 1520-4804
Divisions: Current > QUT Faculties and Divisions > Science & Engineering Faculty
Deposited On: 04 Apr 2016 23:02
Last Modified: 27 Jun 2017 08:01

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