2-Amino-3,4-dihydroquinazolines as Inhibitors of BACE-1 (-Site APP Cleaving Enzyme): Use of Structure Based Design to

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• 作者：Ellen W. Baxter ; Kelly A. Conway ; Ludo Kennis ; Franç ; ois Bischoff ; Marc H. Mercken ; Hans L. De Winter ; Charles H. Reynolds ; Brett A. Tounge ; Chi Luo ; Malcolm K. Scott ; Yifang Huang ; Mirielle Bra
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：September 6, 2007
• 年：2007
• 卷：50
• 期：18
• 页码：4261 - 4264
• 全文大小：155K
• 年卷期：v.50,no.18(September 6, 2007)
• ISSN：1520-4804

文摘

A new aspartic protease inhibitory chemotype bearing a2-amino-3,4-dihydroquinazoline ring was identified by high-throughputscreening for the inhibition of BACE-1. X-ray crystallography revealedthat the exocyclic amino group participated in a hydrogen bonding arraywith the two catalytic aspartic acids of BACE-1 (Asp₃₂, Asp₂₂₈).BACE-1 inhibitory potency was increased (0.9 M to 11 nM K_i) bysubstitution into the unoccupied S₁' pocket.