(S)-N-(5-Chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing gamma-secretase inhibitor

Bioorg Med Chem Lett. 2009 Feb 1;19(3):926-9. doi: 10.1016/j.bmcl.2008.11.116. Epub 2008 Dec 6.

Abstract

Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.

MeSH terms

  • Alcohols
  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / chemistry
  • Animals
  • Drug Design
  • Humans
  • Isoleucine / analogs & derivatives*
  • Isoleucine / chemistry
  • Models, Chemical
  • Propanolamines / chemistry
  • Receptor, Notch1 / metabolism*
  • Sulfonamides / chemistry

Substances

  • (S)-4-chlorophenylsulfonyl isoleucinol
  • Alcohols
  • Amyloid beta-Protein Precursor
  • Propanolamines
  • Receptor, Notch1
  • Sulfonamides
  • Isoleucine
  • isoleucinol
  • 2-aminopropanol
  • Amyloid Precursor Protein Secretases