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)

被引：13

作者：

O'Neill, David J. ^{[1
]}

Adedoyin, Adedayo ^{[3
]}

Alfinito, Peter D. ^{[2
]}

Bray, Jenifer A. ^{[2
]}

Cosmi, Scott ^{[2
]}

Deecher, Darlene C. ^{[2
]}

Fensome, Andrew ^{[1
]}

Harrison, Jim ^{[4
]}

Leventhal, Liza ^{[4
]}

Mann, Charles ^{[1
]}

McComas, Casey C. ^{[1
]}

Sullivan, Nicole R. ^{[4
]}

Spangler, Taylor B. ^{[4
]}

Uveges, Albert J. ^{[4
]}

Trybulski, Eugene J. ^{[1
]}

Whiteside, Garth T. ^{[4
]}

Zhang, Puwen ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Chem Sci, Collegeville, PA 19426 USA

[2] Pfizer Global Res & Dev, Musculoskeletal Biol, Collegeville, PA 19426 USA

[3] Pfizer Global Res & Dev, Drug Safety & Metab, Collegeville, PA 19426 USA

[4] PGRD, Neurosci, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 11期

关键词：

NEUROTRANSMITTER TRANSPORTERS; DESCENDING MODULATION; RODENT MODELS; CHRONIC PAIN; ANTIDEPRESSANT; FIBROMYALGIA; REBOXETINE; AGONIST;

D O I：

10.1021/jm100053t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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(3H)-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 S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hsERT (> 1600-fold) and hDAT (> 600-fold). S-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.

引用

页码：4511 / 4521

页数：11

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