1. Discovery of furo[2,3-d][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitors.
- Author
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Wu YJ, Guernon J, Rajamani R, Toyn JH, Ahlijanian MK, Albright CF, Muckelbauer J, Chang C, Camac D, Macor JE, and Thompson LA
- Subjects
- Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases chemistry, Amyloid Precursor Protein Secretases metabolism, Aspartic Acid Endopeptidases chemistry, Aspartic Acid Endopeptidases metabolism, Catalytic Domain, Humans, Models, Molecular, Protein Binding, Alzheimer Disease drug therapy, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Furans chemistry, Furans pharmacology, Thiazines chemistry, Thiazines pharmacology
- Abstract
This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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