Design and synthesis of water soluble β-aminosulfone analogues of SCH 900229 as γ-secretase inhibitors

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5836-5841. doi: 10.1016/j.bmcl.2016.04.095. Epub 2016 May 7.

Abstract

In this paper we describe our strategy to improve the aqueous solubility of SCH 900229, a potent PS1-selective γ-secretase inhibitor for the treatment of Alzheimer's disease. Incorporation of ionizable amino groups into the side chain terminal generates water soluble β-aminosulfone analogues of SCH 900229 that maintain robust in vitro potency and in vivo efficacy.

Keywords: Alzheimer’s disease; Aqueous solubility; β-Aminosulfone; γ-Secretase inhibitor.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / enzymology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Benzopyrans / chemistry*
  • Benzopyrans / pharmacokinetics
  • Benzopyrans / pharmacology*
  • Dogs
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Haplorhini
  • Humans
  • Rats
  • Solubility
  • Sulfones / chemistry*
  • Sulfones / pharmacokinetics
  • Sulfones / pharmacology*
  • Water / chemistry

Substances

  • Benzopyrans
  • Enzyme Inhibitors
  • SCH 900229
  • Sulfones
  • Water
  • Amyloid Precursor Protein Secretases