Preparation and biological evaluation of conformationally constrained BACE1 inhibitors. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Winneroski, Leonard L.; Schiffler, Matthew A.; Erickson, Jon A.; May, Patrick C.; Monk, Scott A.; Timm, David E.; Audia, James E.; Beck, James P.; Boggs, Leonard N.; Borders, Anthony R.; Boyer, Robert D.; Brier, Richard A.; Hudziak, Kevin J.; Klimkowski, Valentine J.; Garcia Losada, Pablo; Mathes, Brian M.; Stout, Stephanie L.; Watson, Brian M.; Mergott, Dustin J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3260
• Page End: 3268
• Publication Date: 2015-07-01
• Subjects: MBP maltose binding protein -- mcaFRET (7-methoxycoumarin-4-yl)acetyl modified fluorescence resonance energy transfer -- MDCK Madin-Darby canine epithelial cells -- NT not tested -- PDAPP transgenic mice overexpressing mutant human amyloid precursor protein V717F; BACE inhibitor -- Complex organic synthesis -- Conformational constraint -- Stereoselective -- Structure-based drug design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.04.062
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of3 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 inhibitor6, which informed the S3-design for constrained analogs7 and8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors6 –8 is described.