Adenosine analogue inhibitors of S-adenosylhomocysteine hydrolase

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 12; pp. 2737 - 2740
• Main Authors: Converso, Antonella, Hartingh, Timothy, Fraley, Mark E., Garbaccio, Robert M., Hartman, George D., Huang, Shaei Y., Majercak, John M., McCampbell, Alexander, Na, Sang Jin, Ray, William J., Savage, Mary J., Wolffe, Carrie, Yeh, Suzie, Yu, Yuanjiang, White, Rebecca, Zhang, Rena
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.06.2014; Elsevier
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemistry; Adenosine - pharmacology; Adenosine analogues; AHCY; Alzheimer’s disease; Animals; Brain Chemistry; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Design; Enzyme Activation - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Homocysteine; Homocysteine - blood; Hydrogen Bonding; Hydrolases - antagonists & inhibitors; Inhibitory Concentration 50; Life Sciences & Biomedicine; Models, Molecular; Pharmacology & Pharmacy; Physical Sciences; Rats; S-Adenosylhomocysteine - chemistry; SAH; Science & Technology; Substrate Specificity; AHCY; SAH; Alzheimer’s disease; Homocysteine; Adenosine analogues; NEPLANOCIN-A; HYPERHOMOCYSTEINEMIA; DEMENTIA; ALZHEIMERS-DISEASE; L-HOMOCYSTEINE; Alzheimer's disease
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.04.034

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.