甲基磺酰基吡唑并噁二唑和噻二唑类化合物作为有效的、口服生物利用度的大麻素-1 受体拮抗剂，用于治疗肥胖症。
Methylsulfonylpyrazolyl oxadiazoles and thiadiazoles as potent, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity.
机构信息
Central Research Laboratories, Green Cross Corporation, 303 Bojeong-dong, Giheung-gu, Yongin 446-770, Korea.
出版信息
Future Med Chem. 2009 Aug;1(5):947-67. doi: 10.4155/fmc.09.64.
BACKGROUND
Since the cannabinoid receptor 1 (CB1) 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.
DISCUSSION
In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity.
RESULTS
The structure-activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC(50) values of approximately 1 nM for the rat CB1 receptor binding. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.
背景
先前有报道称大麻素受体 1（CB1）拮抗剂 SR141716（利莫那班）可调节食物摄入，因此 CB1 拮抗作用被认为是治疗肥胖的新治疗靶点。
讨论
本研究合成了基于含硫吡唑核心的联苯吡唑类似物，并与 1,3,4-噁二唑和 1,3,4-噻二唑偶联，检测了它们对大鼠 CB1 受体的结合亲和力。
结果
通过优化吡唑取代基以及 1,3,4-噁二唑或 1,3,4-噻二唑环的构效关系研究，得到了四个新型 CB1 拮抗剂，它们对大鼠 CB1 受体的结合具有约 1 nM 的 IC50 值。在这些衍生物中，我们鉴定出三氟甲基环丁基类似物 19e 和 19l 作为有前途的抗肥胖药物开发前体候选物。
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