title: 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.
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 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 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.
authors.affiliation: Zydus Research Centre, Sarkhej-Bavla N. H. 8A, Moraiya, Ahmedabad 382210, India. brijeshsrivastava@zyduscadila.com
authors.forename: Brijesh Kumar
authors.initials: BK
authors.lastname: Srivastava
authors.forename: Amit
authors.initials: A
authors.lastname: Joharapurkar
authors.forename: Saurin
authors.initials: S
authors.lastname: Raval
authors.forename: Jayendra Z
authors.initials: JZ
authors.lastname: Patel
authors.forename: Rina
authors.initials: R
authors.lastname: Soni
authors.forename: Preeti
authors.initials: P
authors.lastname: Raval
authors.forename: Archana
authors.initials: A
authors.lastname: Gite
authors.forename: Amitgiri
authors.initials: A
authors.lastname: Goswami
authors.forename: Nisha
authors.initials: N
authors.lastname: Sadhwani
authors.forename: Neha
authors.initials: N
authors.lastname: Gandhi
authors.forename: Harilal
authors.initials: H
authors.lastname: Patel
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Mishra
authors.forename: Manish
authors.initials: M
authors.lastname: Solanki
authors.forename: Bipin
authors.initials: B
authors.lastname: Pandey
authors.forename: Mukul R
authors.initials: MR
authors.lastname: Jain
authors.forename: Pankaj R
authors.initials: PR
authors.lastname: Patel
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001067:Appetite Depressants / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D005260:Female; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: C482795:3-(4-chlorophenyl)-N-methyl-N'-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine; D000577:Amides; D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D009025:Morpholines; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides; D000077285:Rimonabant