Adenosine analogue inhibitors of S-adenosylhomocysteine hydrolase

Bioorg Med Chem Lett. 2014 Jun 15;24(12):2737-40. doi: 10.1016/j.bmcl.2014.04.034. Epub 2014 Apr 18.

Abstract

Elevated plasma homocysteine (Hcy) levels are an independent risk factor for the onset and progression of Alzheimer's disease. Reduction of Hcy to normal levels therefore presents a new approach for disease modification. Hcy is produced by the cytosolic enzyme S-adenosylhomocysteine hydrolase (AHCY), which converts S-adenosylhomocysteine (SAH) to Hcy and adenosine. Herein we describe the design and characterization of novel, substrate-based S-adenosylhomocysteine hydrolase inhibitors with low nanomolar potency in vitro and robust activity in vivo.

Keywords: AHCY; Adenosine analogues; Alzheimer’s disease; Homocysteine; SAH.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Animals
  • Brain Chemistry
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Homocysteine / blood
  • Hydrogen Bonding
  • Hydrolases / antagonists & inhibitors*
  • Inhibitory Concentration 50
  • Models, Molecular
  • Rats
  • S-Adenosylhomocysteine* / chemistry
  • Substrate Specificity

Substances

  • Enzyme Inhibitors
  • Homocysteine
  • neplanocin A
  • S-Adenosylhomocysteine
  • Hydrolases
  • Adenosine