Discovery of Novel Selective Norepinephrine Inhibitors: 1-(2-Morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-Dioxides (WYE-114152)

详细信息    查看全文

• 作者：David J. O鈥橬eill ; Adedayo Adedoyin ; Jenifer A. Bray ; Darlene C. Deecher ; Andrew Fensome ; Joel A. Goldberg ; Jim Harrison ; Liza Leventhal ; Charles Mann ; Lilly Mark ; Lisa Nogle ; Nicole R. Sullivan ; Taylor B. Spangler ; Eugene A. Terefenko ; Eugene J. Trybulski ; Albert J. Uveges ; An Vu ; Garth T. Whiteside ; Puwen Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6824-6831
• 全文大小：935K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC₅₀ = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.