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

Adenosine analogue inhibitors of S-adenosylhomocysteine hydrolase.

Author information

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.

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

PMID:
24813734
DOI:
10.1016/j.bmcl.2014.04.034
[Indexed for MEDLINE]

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