2. Academic Validation
  3. Adenosine analogue inhibitors of S-adenosylhomocysteine hydrolase

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

Affiliations

  • 1 Medicinal Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: antonella_converso@merck.com.
  • 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.

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