Adenosine analogue inhibitors of S-adenosylhomocysteine hydrolase

Antonella Converso; Timothy Hartingh; Mark E Fraley; Robert M Garbaccio; George D Hartman; Shaei Y Huang; John M Majercak; Alexander McCampbell; Sang Jin Na; William J Ray; Mary J Savage; Carrie Wolffe; Suzie Yeh; Yuanjiang Yu; Rebecca White; Rena Zhang

doi:10.1016/j.bmcl.2014.04.034

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.

Authors

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.

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