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.
Antonella Converso  1 ,  Timothy Hartingh  2 ,  Mark E Fraley  2 ,  Robert M Garbaccio  2 ,  George D Hartman  2 ,  Shaei Y Huang  2 ,  John M Majercak  3 ,  Alexander McCampbell  4 ,  Sang Jin Na  3 ,  William J Ray  4 ,  Mary J Savage  4 ,  Carrie Wolffe  3 ,  Suzie Yeh  5 ,  Yuanjiang Yu  3 ,  Rebecca White  5 ,  Rena Zhang  5
Affiliations
  • 1. Medicinal Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: [email protected].
  • 2. Medicinal Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • 3. In Vitro Pharmacology Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • 4. Neuroscience Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • 5. Pharmacokinetics, Pharmacodynamics, and Drug Metabolism Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
PMID: 24813734 DOI: 10.1016/j.bmcl.2014.04.034
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.