title: Asymmetric synthesis and biological evaluation of N-cyclohexyl-4-[1-(2,4-dichlorophenyl)-1-(p-tolyl)methyl]piperazine-1-carboxamide as hCB1 receptor antagonists.
abstract: We recently discovered and reported a novel series of benzhydrylpiperazine derivatives bearing an asymmetric carbon atom that are potent and selective hCB1 inverse agonists. In the present study, we used Davis-Ellmann-type sulfonamide chemistry to asymmetrically synthesize two enantiomers of the most potent racemic N-cyclohexyl-4-[1-(2,4-dichlorophenyl)-1-(p-tolyl)methyl]piperazine-1-carboxamide [14]. Enantiomer separation and configuration assignment were carried out. Our results indicate that the R-configuration is the more active enantiomer, displaying enhanced antagonistic activity for hCB1 receptor, better oral bioavailability, and greater efficacy in the reduction of body weight in diet-induced obese mice.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203.
authors.forename: Linghuan
authors.initials: L
authors.lastname: Gao
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Meng
authors.forename: Hongli
authors.initials: H
authors.lastname: Peng
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Jin
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Libo
authors.initials: L
authors.lastname: Zou
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D016466:CHO Cells; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D006224:Cricetinae; D003412:Cricetulus; D008297:Male; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry
chemical_list: C569928:N-cyclohexyl-4-(1-(2,4-dichlorophenyl)-1-(p-tolyl)methyl)piperazine-1-carboxamide; D010879:Piperazines; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides