Discovery of benzhydrylpiperazine derivatives as CB1 receptor inverse agonists via privileged structure-based approach.
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.
Meng
Tao
T
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
Wang
Jue
J
Peng
Hongli
H
Fang
Guanghua
G
Li
Min
M
Xiong
Bing
B
Xie
Xin
X
Zhang
Yongliang
Y
Wang
Xin
X
Shen
Jingkang
J
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
D001559:Benzhydryl Compounds; D010879:Piperazines; D043884:Receptor, Cannabinoid, CB1; D011994:Recombinant Proteins