Spirocyclic sulfamides as β-secretase 1 (BACE-1) inhibitors for the treatment of Alzheimer's disease: utilization of structure based drug design, WaterMap, and CNS penetration studies to identify centrally efficacious inhibitors

J Med Chem. 2012 Nov 8;55(21):9224-39. doi: 10.1021/jm3009426. Epub 2012 Oct 8.

Abstract

β-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize central nervous system (CNS) penetration by minimizing hydrogen bond donors (HBDs) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogues and the in silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central Aβ(X-40) levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies of the P-gp knockout mouse provided evidence that efflux transporters affected the amount of Aβ lowering versus that observed in wild-type (WT) mouse at an equivalent dose.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / chemistry
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / pharmacokinetics
  • Aza Compounds / pharmacology
  • Brain / metabolism*
  • Crystallography, X-Ray
  • Dogs
  • Drug Design
  • Female
  • Humans
  • Madin Darby Canine Kidney Cells
  • Male
  • Mice
  • Mice, Knockout
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Permeability
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology
  • Transfection

Substances

  • 4-(((5R,7S)-1-(3-fluorophenyl)-3,7-dimethyl-2,2-dioxido-2-thia-1,3,8-triazaspiro(4,5)dec-8-yl)methyl)-2-isopropoxyphenol
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Amyloid beta-Peptides
  • Aza Compounds
  • Spiro Compounds
  • Sulfonamides
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human

Associated data

  • PDB/4FM7
  • PDB/4FM8