Song Kwang-Seop, Lee Sung-Han, Chun Hyun Ji, Kim Jong Yup, Jung Myung Eun, Ahn Kwangwoo, Kim Soo-Un, Kim Jeongmin, Lee Jinhwa
Small Molecule Group, Central Research Institute, Green Cross Corporation, 341 Bojeong-dong, Giheung-gu, Yongin, Gyunggi-do 446-799, Republic of Korea.
Bioorg Med Chem. 2008 Apr 1;16(7):4035-51. doi: 10.1016/j.bmc.2008.01.023. Epub 2008 Jan 19.
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 IC(50) values less than 100 nM for the CB1 receptor binding.
此前有报道称，CB1受体拮抗剂SR141716（利莫那班）可调节食物摄入量，因此CB1拮抗作用已被视为治疗肥胖症的新治疗靶点。基于1-二苯甲基哌嗪骨架合成了几个系列的尿素、氨基甲酸酯、酰胺、磺酰胺和草酰胺衍生物，并测试了它们对CB1受体的结合亲和力。为优化CB1结合亲和力而进行的构效关系（SAR）研究产生了强效的尿素衍生物。在进一步进行SAR研究以优化二苯环的取代基后，2-氯苯基和4-氯苯基的组合被证明是最有效的骨架。还对这些化合物进行了CB2结合亲和力测定以及功能测定。在此，我们希望介绍几种新型CB1拮抗剂，它们对CB1受体结合的IC(50)值小于100 nM。
