Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain A? Reduction in Rodents [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 547 Organic chemistry
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 271-276 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 261020
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 60 applied life sciences; 3. A?42; 4. Alzheimer?s disease; 5. Aminothiazine; 6. Amyloid hypothesis; 7. Bace1; 8. Inhibitor

Tóm tắt

 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 (IC<
 sub>
 50<
 /sub>
  <
  1 nM). This compound demonstrated robust brain A? reduction in rat dose?response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer?s disease.