title: Discovery of benzhydrylpiperazine derivatives as CB1 receptor inverse agonists via privileged structure-based approach.
abstract: The present study describes the identification via privileged structure-based approach of the benzhydrylpiperazine moiety as a potential scaffold to develop novel CB(1) receptor modulators. Efficient structural optimization of the initial four hit compounds led to a high quality lead series, represented by compound 6c. Compound 6c is a highly potent and selective CB(1) receptor inverse agonist that is able to reduce body weight in diet-induced obese Sprague-Dawley rats. The preparation of privileged structure-based library, the progression from hit to lead, the structure-activity relationships in the lead series and in vitro and in vivo activity of compound 6c are discussed.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Meng
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Hongli
authors.initials: H
authors.lastname: Peng
authors.forename: Guanghua
authors.initials: G
authors.lastname: Fang
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.forename: Xin
authors.initials: X
authors.lastname: Xie
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D001559:Benzhydryl Compounds; D010879:Piperazines; D043884:Receptor, Cannabinoid, CB1; D011994:Recombinant Proteins