Novel orally bioavailable gamma-secretase inhibitors with excellent in vivo activity

J Med Chem. 2009 Jun 11;52(11):3441-4. doi: 10.1021/jm900056p.

Abstract

The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED(50) of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.

MeSH terms

  • Administration, Oral
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Animals
  • Cyclooctanes / administration & dosage
  • Cyclooctanes / chemical synthesis
  • Cyclooctanes / pharmacokinetics
  • Cyclooctanes / pharmacology*
  • Inhibitory Concentration 50
  • Mice
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / pharmacokinetics
  • Protease Inhibitors / pharmacology*
  • Thiadiazoles / administration & dosage
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / pharmacokinetics
  • Thiadiazoles / pharmacology*

Substances

  • 2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro(6,9-methanobenzocycloocten-11,3'-(1,2,5)thiadiazole) 1',1'-dioxide
  • Amyloid beta-Peptides
  • Cyclooctanes
  • Protease Inhibitors
  • Thiadiazoles
  • Amyloid Precursor Protein Secretases