Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.
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.
['Winneroski|Leonard L|LL|', 'Schiffler|Matthew A|MA|', 'Erickson|Jon A|JA|', 'May|Patrick C|PC|', 'Monk|Scott A|SA|', 'Timm|David E|DE|', 'Audia|James E|JE|', 'Beck|James P|JP|', 'Boggs|Leonard N|LN|', 'Borders|Anthony R|AR|', 'Boyer|Robert D|RD|', 'Brier|Richard A|RA|', 'Hudziak|Kevin J|KJ|', 'Klimkowski|Valentine J|VJ|', 'Garcia Losada|Pablo|P|', 'Mathes|Brian M|BM|', 'Stout|Stephanie L|SL|', 'Watson|Brian M|BM|', 'Mergott|Dustin J|DJ|']
D053829:Amyloid Precursor Protein Secretases D000818:Animals D016282:Aspartic Acid Endopeptidases D001923:Brain Chemistry D001643:Bridged Bicyclo Compounds D018360:Crystallography, X-Ray D015195:Drug Design D006801:Humans D051379:Mice D008968:Molecular Conformation D062105:Molecular Docking Simulation D011480:Protease Inhibitors D013237:Stereoisomerism D013843:Thiazines
Conformational constraint BACE inhibitor Complex organic synthesis Stereoselective Structure-based drug design