Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease

被引：88

作者：

Mayer, Scott C. ^{[1
]}

Kreft, Anthony F. ^{[1
]}

Harrison, Boyd ^{[1
]}

Abou-Gharbia, Magid ^{[1
]}

Antane, Madelene ^{[1
]}

Aschmies, Suzan ^{[2
]}

Atchison, Kevin ^{[2
]}

Chlenov, Michael ^{[1
]}

Cole, Derek C. ^{[1
]}

Comery, Thomas ^{[2
]}

Diamantidis, George ^{[1
]}

Ellingboe, John ^{[1
]}

Fan, Kristi ^{[1
]}

Galante, Rocco ^{[1
]}

Gonzales, Cathleen ^{[2
]}

Ho, Douglas M. ^{[6
]}

Hoke, Molly E. ^{[1
]}

Hu, Yun ^{[2
]}

Huryn, Donna ^{[1
]}

Jain, Uday ^{[1
]}

Jin, Mei ^{[2
]}

Kremer, Kenneth ^{[1
]}

Kubrak, Dennis ^{[1
]}

Lin, Melissa ^{[1
]}

Lu, Peimin ^{[2
]}

Magolda, Ron ^{[1
]}

Martone, Robert ^{[2
]}

Moore, William ^{[5
]}

Oganesian, Aram ^{[4
]}

Pangalos, Menelas N. ^{[2
]}

Porte, Alex ^{[1
]}

Reinhart, Peter ^{[2
]}

Resnick, Lynn ^{[1
]}

Riddell, David R. ^{[2
]}

Sonnenberg-Reines, June ^{[2
]}

Stock, Joseph R. ^{[1
]}

Sun, Shaiu-Ching ^{[2
]}

Wagner, Erik ^{[2
]}

Wang, Ting ^{[3
]}

Woller, Kevin ^{[5
]}

Xu, Zheng ^{[2
]}

Zaleska, Margaret M. ^{[2
]}

Zeldis, Joseph ^{[3
]}

Zhang, Minsheng ^{[1
]}

Zhou, Hua ^{[2
]}

Jacobsen, J. Steven ^{[2
]}

机构：

[1] Wyeth Ayerst Res, Chem & Screening Sci, Princeton, NJ 08543 USA

[2] Wyeth Ayerst Res, Discovery Neurosci, Princeton, NJ 08543 USA

[3] Wyeth Ayerst Res, Chem Dev, Pearl River, NY 10965 USA

[4] Wyeth Ayerst Res, Drug Safety & Metab, Collegeville, PA 19426 USA

[5] ArQule Inc, Div Chem Technol, Woburn, MA 01801 USA

[6] Harvard Univ, Cambridge, MA 02138 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 23期

关键词：

D O I：

10.1021/jm801252w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SAR on HTS hits I and 2 led to the potent, Notch-l-sparing GSI 9, which lowered brain A beta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5). which was selected for development for the treatment of Alzheimer's disease.

引用

页码：7348 / 7351

页数：4

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