Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

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• 作者：Yong-Jin Wu ; Jason Guernon ; Fukang Yang ; Lawrence Snyder ; Jianliang Shi ; Andrea Mcclure ; Ramkumar Rajamani ; Hyunsoo Park ; Alicia Ng ; Hal Lewis ; ChiehYing Chang ; Dan Camac ; Jeremy H. Toyn ; Michael K. Ahlijanian ; Charles F. Albright ; John E. Macor ; Lorin A. Thompson
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：271-276
• 全文大小：433K
• ISSN：1948-5875

文摘

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC₅₀ < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose–response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer’s disease.