1. Preparation and biological evaluation of conformationally constrained BACE1 inhibitors
- Author
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Stephanie L. Stout, Patrick C. May, Brian Morgan Watson, Pablo Garcia Losada, Valentine J. Klimkowski, Brian Michael Mathes, David E. Timm, Dustin J. Mergott, Scott A. Monk, Leonard L. Winneroski, Leonard N. Boggs, James P. Beck, James E. Audia, Matthew Allen Schiffler, Richard A. Brier, Anthony R. Borders, Jon A. Erickson, Robert D. Boyer, and Kevin John Hudziak
- Subjects
Stereochemistry ,Clinical Biochemistry ,Molecular Conformation ,Thiazines ,Pharmaceutical Science ,Crystallography, X-Ray ,Biochemistry ,chemistry.chemical_compound ,Bridged Bicyclo Compounds ,Mice ,Thiazine ,mental disorders ,Drug Discovery ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Protease Inhibitors ,Molecular Biology ,Biological evaluation ,chemistry.chemical_classification ,Medicine(all) ,Brain Chemistry ,Bicyclic molecule ,Organic Chemistry ,Stereoisomerism ,Molecular Docking Simulation ,Enzyme ,chemistry ,Drug Design ,Molecular Medicine ,Stereoselectivity ,Amyloid Precursor Protein Secretases - Abstract
The BACE1 enzyme is a key target for Alzheimer’s disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6–8 is described.
- Published
- 2015