Weber A E, Mathvink R J, Perkins L, Hutchins J E, Candelore M R, Tota L, Strader C D, Wyvratt M J, Fisher M H
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Bioorg Med Chem Lett. 1998 May 5;8(9):1101-6. doi: 10.1016/s0960-894x(98)00169-3.
A cloned human beta 3 adrenergic receptor assay was used to identify phenoxypropanolamine agonist 1. SAR studies led to the identification of benzenesulfonamide derivative 20, a 6.3 nM beta 3 agonist which shows 30-fold selectivity for beta 3 agonist activity over beta 1 and beta 2 receptor binding. Further refinement of this lead provided 4-bromo derivative 39, a subnanomolar agonist with 660-fold and 230-fold selectivity over beta 1 and beta 2, respectively.
采用克隆的人β3肾上腺素能受体分析方法来鉴定苯氧丙醇胺激动剂1。构效关系研究促使鉴定出苯磺酰胺衍生物20，这是一种6.3 nM的β3激动剂，其对β3激动剂活性的选择性比对β1和β2受体结合高30倍。对该先导化合物的进一步优化得到了4-溴衍生物39，这是一种亚纳摩尔级激动剂，对β1和β2的选择性分别为660倍和230倍。
