Fluorinated piperidine acetic acids as gamma-secretase modulators

Bioorg Med Chem Lett. 2010 Jan 15;20(2):755-8. doi: 10.1016/j.bmcl.2009.11.034. Epub 2009 Nov 13.

Abstract

We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.

MeSH terms

  • Acetates / chemical synthesis
  • Acetates / chemistry*
  • Acetates / pharmacokinetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Diazonium Compounds / chemistry
  • Disease Models, Animal
  • Fluorine / chemistry*
  • Mice
  • Mice, Transgenic
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Rats
  • Receptors, Notch / metabolism

Substances

  • Acetates
  • Amyloid beta-Peptides
  • Diazonium Compounds
  • Peptide Fragments
  • Piperidines
  • Receptors, Notch
  • amyloid beta-protein (1-42)
  • Fluorine
  • selectfluor
  • Amyloid Precursor Protein Secretases