Zhu Cheng, Kar Nam F, Li Bing, Costa Melissa, Dingley Karen H, Di Salvo Jerry, Ha Sookhee N, Hurley Amanda L, Li Xiaofang, Miller Randy R, Salituro Gino M, Struthers Mary, Weber Ann E, Hale Jeffrey J, Edmondson Scott D
Early Development and Discovery Sciences, Merck and Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Early Development and Discovery Sciences, Merck and Co., Inc., 126 East Lincoln Avenue, Rahway, NJ 07065, United States.
Bioorg Med Chem Lett. 2016 Jan 1;26(1):55-9. doi: 10.1016/j.bmcl.2015.11.030. Epub 2015 Nov 11.
The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human β3-adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was synthesized. From library synthesis and further optimization efforts, several structurally diverse reverse amides such as 24c and 24i were found to have excellent human β3-adrenergic potency and good selectivity over the β1 and β2 receptors. In addition to human β1, β2, β3 and hERG data, PK of selected compounds will be described.
本文将描述导致发现苯甲酰胺（反向酰胺）作为强效且选择性的人β3-肾上腺素能受体激动剂的合成及构效关系研究。基于我们之前发现的构象受限的吡咯烷骨架，合成了吡咯烷苯甲酸中间体22。通过库合成及进一步优化，发现了几种结构多样的反向酰胺，如24c和24i，它们对人β3-肾上腺素能具有优异的活性，且对β1和β2受体具有良好的选择性。除了人β1、β2、β3和hERG数据外，还将描述所选化合物的药代动力学。
