Vachal Petr, Fletcher Joan M, Fong Tung M, Huang Cathy C R-R, Lao Julie, Xiao Jing C, Shen Chun-Pyn, Strack Alison M, Shearman Lauren, Stribling Sloan, Chen Richard Z, Frassetto Andrea, Tong Xinchun, Wang Junying, Ball Richard G, Tsou Nancy N, Hickey Gerard J, Thompson Donald F, Faidley Terry D, Nicolich Susan, Achanfuo-Yeboah Joana, Hora Donald F, Hale Jeffrey J, Hagmann William K
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
J Med Chem. 2009 Apr 23;52(8):2550-8. doi: 10.1021/jm900063x.
A novel series of 1-sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists was discovered through high throughput screening (HTS) and medicinal chemistry lead optimization. Potency and in vivo properties were systematically optimized to afford orally bioavailable, highly efficacious, and selective CB1R inverse agonists that caused food intake suppression and body weight reduction in diet-induced obese rats and dogs. It was found that the receptor binding assay predicted in vivo efficacy better than functional antagonist/inverse agonist activities. This observation expedited the structure-activity relationship (SAR) analysis and may have implications beyond the series of compounds presented herein.
通过高通量筛选（HTS）和药物化学先导物优化，发现了一系列新型的1-磺酰基-4-酰基哌嗪作为选择性大麻素-1受体（CB1R）反向激动剂。对效力和体内性质进行了系统优化，以提供口服生物利用度高、高效且选择性的CB1R反向激动剂，这些激动剂可导致饮食诱导的肥胖大鼠和狗的食物摄入量减少和体重减轻。发现受体结合试验比功能性拮抗剂/反向激动剂活性更能预测体内疗效。这一观察结果加快了构效关系（SAR）分析，并且可能在此处呈现的一系列化合物之外具有更广泛的意义。
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