Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme

Bioorg Med Chem Lett. 2016 Aug 15;26(16):3928-37. doi: 10.1016/j.bmcl.2016.07.011. Epub 2016 Jul 6.

Abstract

The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aβ42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds.

Keywords: Alzheimer’s disease; Aminothiazoles; γ-Secretase modulators.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Drug Design*
  • Half-Life
  • Humans
  • Kinetics
  • Male
  • Mice
  • Microsomes, Liver / metabolism
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Rats
  • Solubility
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / pharmacokinetics

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Thiazoles
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases