Small conformationally restricted piperidine N-arylsulfonamides as orally active gamma-secretase inhibitors

Bioorg Med Chem Lett. 2007 Oct 1;17(19):5330-5. doi: 10.1016/j.bmcl.2007.08.013. Epub 2007 Aug 15.

Abstract

The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease.

MeSH terms

  • Administration, Oral
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / biosynthesis
  • Animals
  • Area Under Curve
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Design
  • Magnetic Resonance Spectroscopy
  • Mice
  • Molecular Conformation
  • Molecular Weight
  • Oxidoreductases / metabolism
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacology*
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology*

Substances

  • Amyloid beta-Peptides
  • Piperidines
  • Sulfonamides
  • Cytochrome P-450 Enzyme System
  • Cyp3a41a protein, mouse
  • Oxidoreductases
  • Amyloid Precursor Protein Secretases