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)

被引：11

作者：

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

Adedoyin, Adedayo ^{[3
]}

Bray, Jenifer A. ^{[4
]}

Deecher, Darlene C. ^{[2
]}

Fensome, Andrew ^{[1
]}

Goldberg, Joel A. ^{[1
]}

Harrison, Jim ^{[4
]}

Leventhal, Liza ^{[4
]}

Mann, Charles ^{[1
]}

Mark, Lilly ^{[4
]}

Nogle, Lisa ^{[1
]}

Sullivan, Nicole R. ^{[4
]}

Spangler, Taylor B. ^{[4
]}

Terefenko, Eugene A. ^{[1
]}

Trybulski, Eugene J. ^{[1
]}

Uveges, Albert J. ^{[4
]}

Vu, An ^{[1
]}

Whiteside, Garth T. ^{[4
]}

Zhang, Puwen ^{[1
]}

机构：

[1] Pfizer, Chem Sci, Collegeville, PA 19426 USA

[2] Pfizer, Musculoskeletal Biol, Collegeville, PA 19426 USA

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

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 19期

关键词：

NEUROTRANSMITTER TRANSPORTERS; DESCENDING MODULATION; REUPTAKE INHIBITORS; PAIN; ANTIDEPRESSANT; FIBROMYALGIA; REBOXETINE; AGONIST; MODELS;

D O I：

10.1021/jm200733r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：6824 / 6831

页数：8

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