Discovery of Novel Selective Norepinephrine Reuptake Inhibitors: 4-[3-Aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols (WYE-103231)

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• 作者：David J. O&#8217 ; Neill ; Adedayo Adedoyin ; Peter D. Alfinito ; Jenifer A. Bray ; Scott Cosmi ; Darlene C. Deecher ; Andrew Fensome ; Jim Harrison ; Liza Leventhal ; Charles Mann ; Casey C. McComas ; Nicole R. S
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：June 10, 2010
• 年：2010
• 卷：53
• 期：11
• 页码：4511-4521
• 全文大小：1018K
• 年卷期：v.53,no.11(June 10, 2010)
• ISSN：1520-4804

文摘

Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3<i>Hi>)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound <i>Si>-17b (WYE-103231) had low nanomolar hNET potency (IC₅₀ = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). <i>Si>-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.