From Fragment Screening to In Vivo Efficacy: Optimization of a Series of 2-Aminoquinolines as Potent Inhibitors of Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)

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• 作者：Yuan Cheng ; Ted C. Judd ; Michael D. Bartberger ; James Brown ; Kui Chen ; Robert T. Fremeau ; Jr. ; Dean Hickman ; Stephen A. Hitchcock ; Brad Jordan ; Vivian Li ; Patricia Lopez ; Steven W. Louie ; Yi Luo ; Klaus Michelsen ; Thomas Nixey ; Timothy S. Powers ; Claire Rattan ; E. Allen Sickmier ; David J. St. Jean ; Jr. ; Robert C. Wahl ; Paul H. Wen ; Stephen Wood
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5836-5857
• 全文大小：1447K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2鈥?binding pocket of BACE1 and enhancing the ligand鈥檚 potency. We were able to improve the BACE1 potency to subnanomolar range, over 10⁶-fold more potent than the initial hit (900 渭M). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood鈥揵rain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC₅₀ value of 11 nM on BACE1 and cellular activity of 80 nM. This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of A尾 levels in cerebrospinal fluid (CSF).