Discovery of cyclic sulfone hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure-based design and in vivo reduction of amyloid β-peptides

J Med Chem. 2012 Apr 12;55(7):3364-86. doi: 10.1021/jm300069y. Epub 2012 Mar 21.

Abstract

Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC(50) values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Benzene Derivatives / chemical synthesis
  • Benzene Derivatives / chemistry
  • Benzene Derivatives / pharmacology
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism*
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Cyclic S-Oxides / chemical synthesis*
  • Cyclic S-Oxides / chemistry
  • Cyclic S-Oxides / pharmacology
  • Dogs
  • Drug Design
  • Ethylamines / chemical synthesis*
  • Ethylamines / chemistry
  • Ethylamines / pharmacology
  • Humans
  • Indazoles / chemical synthesis
  • Indazoles / chemistry
  • Indazoles / pharmacology
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology

Substances

  • 3-(4-amino-3-fluoro-5-((1,1,1-trifluoro-3-methoxypropan-2-yl)oxy)benzyl)-5-((3-(tert-butyl)benzyl)amino)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide
  • 3-(4-amino-3-fluoro-5-(2,2,2-trifluoroethoxy)benzyl)-5-((3-(tert-butyl)benzyl)amino)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide
  • Amyloid beta-Peptides
  • Benzene Derivatives
  • Cyclic S-Oxides
  • Ethylamines
  • Indazoles
  • Indoles
  • Spiro Compounds
  • Sulfones
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse

Associated data

  • PDB/3VEU
  • PDB/3VF3
  • PDB/3VG1
  • PDB/4D83
  • PDB/4D85
  • PDB/4D88
  • PDB/4D89
  • PDB/4D8C