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

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Tác giả:

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

 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.
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