title: 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.
authors.affiliation: Medicinal Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: antonella_converso@merck.com.
authors.forename: Antonella
authors.initials: A
authors.lastname: Converso
authors.affiliation: Medicinal Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hartingh
authors.affiliation: Medicinal Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.affiliation: Medicinal Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.affiliation: Medicinal Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.affiliation: Medicinal Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Shaei Y
authors.initials: SY
authors.lastname: Huang
authors.affiliation: In Vitro Pharmacology Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Majercak
authors.affiliation: Neuroscience Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: McCampbell
authors.affiliation: In Vitro Pharmacology Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Sang Jin
authors.initials: SJ
authors.lastname: Na
authors.affiliation: Neuroscience Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Ray
authors.affiliation: Neuroscience Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Savage
authors.affiliation: In Vitro Pharmacology Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Wolffe
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Suzie
authors.initials: S
authors.lastname: Yeh
authors.affiliation: In Vitro Pharmacology Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Yuanjiang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: White
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Drug Metabolism Department, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Rena
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006710:Homocysteine / Q000097:blood; D006860:Hydrogen Bonding; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D051381:Rats; D012435:S-Adenosylhomocysteine / Q000737:chemistry; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D006710:Homocysteine; C031096:neplanocin A; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D000241:Adenosine
keywords: AHCY; Adenosine analogues; Alzheimer’s disease; Homocysteine; SAH