Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease

被引：12

作者：

Wu, Wen-Lian ^{[1
]}

Domalski, Martin ^{[1
]}

Burnett, Duane A. ^{[1
]}

Josien, Hubert ^{[1
]}

Bara, Thomas ^{[1
]}

Rajagopalan, Murali ^{[1
]}

Xu, Ruo ^{[1
]}

Clader, John ^{[1
]}

Greenlee, William J. ^{[1
]}

Brunskill, Andrew ^{[3
]}

Hyde, Lynn A. ^{[2
]}

Del Vecchio, Robert A. ^{[2
]}

Cohen-Williams, Mary E. ^{[2
]}

Song, Lixin ^{[2
]}

Lee, Julie ^{[2
]}

Terracina, Giuseppe ^{[2
]}

Zhang, Qi ^{[2
]}

Nomeir, Amin ^{[4
]}

Parker, Eric M. ^{[2
]}

Zhang, Lili ^{[2
]}

机构：

[1] Merck Res Labs, Dept Med Chem, Kenilworth, NJ 07033 USA

[2] Merck Res Labs, Dept Neurosci, Kenilworth, NJ 07033 USA

[3] Merck Res Labs, Dept Pharmaceut Sci, Kenilworth, NJ 07033 USA

[4] Merck Res Labs, Dept Drug Metab & Pharmacokinet, Kenilworth, NJ 07033 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 11期

关键词：

gamma-Secretase inhibitor; Alzheimer's disease; amyloid; notch; clinical candidate; TRICYCLIC SULFONES; IN-VIVO; HYPOTHESIS; CONVERSION; ALDEHYDES;

D O I：

10.1021/ml300044f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An exploration of the SAR of the side chain of a novel tricyclic series of gamma-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PSI selective inhibitor of gamma-secretase (A beta 40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of A beta after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.

引用

页码：892 / 896

页数：5

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