Piperidine-derived gamma-secretase modulators

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1306-11. doi: 10.1016/j.bmcl.2009.08.072. Epub 2009 Aug 23.

Abstract

This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.

Publication types

  • Comparative Study

MeSH terms

  • Acetates / chemistry*
  • Acetates / metabolism
  • Acetates / pharmacology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / physiology*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cell Line, Tumor
  • Dogs
  • Humans
  • Mice
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / metabolism
  • Piperidines / chemistry*
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Substrate Specificity / drug effects

Substances

  • (1-(4-methyl-1-(6-(trifluoromethyl)-3-pyridinyl)pentyl)-2-(4-(trifluoromethyl)phenyl)-4-piperidinyl)acetic acid
  • Acetates
  • Amyloid beta-Peptides
  • Peptide Fragments
  • Piperidines
  • amyloid beta-protein (1-38)
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • piperidine
  • Amyloid Precursor Protein Secretases