Preparation and biological evaluation of conformationally constrained BACE1 inhibitors. Issue 13 (1st July 2015) - Winneroski, Leonard L.
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.