Design, synthesis and biological evaluation of piperazine analogues as CB1 cannabinoid receptor ligands
- 作者：Kwang-Seop Song ; Sung-Han Lee ; Hyun Ji Chun ; Jong Yup Kim ; Myung Eun Jung ; Kwangwoo Ahn ; Soo-Un Kim ; Jeongmin Kim ; Jinhwa Lee
- 关键词：CB1 receptor antagonists ; 1-Benzhydrylpiperazine ; SAR study ; Rimonabant ; Piperazine ; Cannabinoid receptor ; Anti-obesity
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2008
- 期刊代码：9_09680896
- 类别：ch
- 出版时间：1 April 2008
- 卷：16
- 期：7
- 页码：4035-4051
- 文件大小：266 K
摘要
After the CB1 receptor antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. Several series of urea, carbamate, amide, sulfonamide and oxalamide derivatives based on 1-benzhydrylpiperazine scaffold were synthesized and tested for CB1 receptor binding affinity. The SAR studies to optimize the CB1 binding affinity led to the potent urea derivatives. After the additional SAR studies to optimize the substituents of diphenyl rings, the combination of 2-chlorophenyl and 4-chlorophenyl turned out to be the most potent scaffold. The CB2 binding affinity assay as well as functional assay was also conducted on these compounds. Herein we wish to introduce several novel CB1 antagonists with IC50 values less than 100 nM for the CB1 receptor binding.