Therapeutic and pharmacokinetic characterizations of an anti-amyloidogenic bis-styrylbenzene derivative for Alzheimer's disease treatment

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3467-9. doi: 10.1016/j.bmcl.2013.02.104. Epub 2013 Mar 13.

Abstract

Alzheimer's disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-β. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F=46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 μM) results indicated safety of KMS80013.

MeSH terms

  • Administration, Oral
  • Alzheimer Disease / drug therapy
  • Aniline Compounds / chemistry*
  • Aniline Compounds / pharmacokinetics
  • Aniline Compounds / therapeutic use
  • Animals
  • Benzene Derivatives / chemistry*
  • Benzene Derivatives / pharmacokinetics
  • Benzene Derivatives / therapeutic use
  • Brain / metabolism
  • Disease Models, Animal
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Half-Life
  • Male
  • Mice
  • Mice, Inbred ICR
  • Stilbenes / chemistry*
  • Stilbenes / pharmacokinetics
  • Stilbenes / therapeutic use

Substances

  • Aniline Compounds
  • Benzene Derivatives
  • Ether-A-Go-Go Potassium Channels
  • KMS80013
  • Stilbenes