Preparation and biological evaluation of conformationally constrained BACE1 inhibitors

Bioorg Med Chem. 2015 Jul 1;23(13):3260-8. doi: 10.1016/j.bmc.2015.04.062. Epub 2015 May 6.

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.

Keywords: BACE inhibitor; Complex organic synthesis; Conformational constraint; Stereoselective; Structure-based drug design.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / isolation & purification
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Aspartic Acid Endopeptidases / isolation & purification
  • Brain Chemistry
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / chemistry
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Mice
  • Molecular Conformation
  • Molecular Docking Simulation
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Stereoisomerism
  • Thiazines / chemical synthesis*
  • Thiazines / chemistry

Substances

  • Bridged Bicyclo Compounds
  • Protease Inhibitors
  • Thiazines
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human