Structure- and Property-Based Design of Aminooxazoline Xanthenes as Selective, Orally Efficacious, and CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer鈥檚 Disease

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• 作者：Hongbing Huang ; Daniel S. La ; Alan C. Cheng ; Douglas A. Whittington ; Vinod F. Patel ; Kui Chen ; Thomas A. Dineen ; Oleg Epstein ; Russell Graceffa ; Dean Hickman ; Y.-H. Kiang ; Steven Louie ; Yi Luo ; Robert C. Wahl ; Paul H. Wen ; Stephen Wood ; Robert T. Fremeau ; Jr.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9156-9169
• 全文大小：571K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human 尾-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS A尾40 in naive rats.