Application of Fragment-Based Lead Generation to the Discovery of Novel, Cyclic Amidine -Secretase Inhibitors with Nanomolar Potency, Cellular Activity, and High Ligand Efficiency

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• 作者：Philip D. Edwards ; Jeffrey S. Albert ; Mark Sylvester ; David Aharony ; Donald Andisik ; Owen Callaghan ; James B. Campbell ; Robin A. Carr ; Gianni Chessari ; Miles Congreve ; Martyn Frederickson ; Rutger H. A
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：5912 - 5925
• 全文大小：359K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitorsof -secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency wereidentified via NMR affinity screening. Structure-guided evolution of these fragments using X-raycrystallography together with potency determination using surface plasmon resonance and functional enzymeinhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to theidentification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of theligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficientlyoptimized to submicromolar potency. Compound 29, with an IC₅₀ of 80 nM, a ligand efficiency of 0.37,and cellular activity of 470 nM, emerged as the lead structure for future optimization.