Adenosine analogue inhibitors of S-adenosylhomocysteine hydrolase.

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.