Antagonists of the human A(2A) adenosine receptor. 4. Design, synthesis, and preclinical evaluation of 7-aryltriazolo[4,5-d]pyrimidines

Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, deplet...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2009-01, Vol.52 (1), p.33
Main Authors: Gillespie, Roger J, Bamford, Samantha J, Botting, Ruth, Comer, Mike, Denny, Sarah, Gaur, Suneel, Griffin, Michael, Jordan, Allan M, Knight, Anthony R, Lerpiniere, Joanne, Leonardi, Stefania, Lightowler, Sean, McAteer, Steven, Merrett, Angela, Misra, Anil, Padfield, Antony, Reece, Mark, Saadi, Mona, Selwood, Daniel L, Stratton, Gemma C, Surry, Dominic, Todd, Richard, Tong, Xin, Ruston, Vicki, Upton, Rebecca, Weiss, Scott M
Format: Article
Language:English
Subjects:
Adenosine A2 Receptor Antagonists
Amines - chemistry
Animals
Azoles - chemical synthesis
Azoles - chemistry
Azoles - pharmacology
Azoles - therapeutic use
Drug Design
Drug Evaluation, Preclinical
Gait Disorders, Neurologic - chemically induced
Gait Disorders, Neurologic - drug therapy
Haloperidol - pharmacology
Humans
Mice
Molecular Structure
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
Rats
Receptor, Adenosine A2A - classification
Receptor, Adenosine A2A - metabolism
Structure-Activity Relationship
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.
ISSN:1520-4804
DOI:10.1021/jm800961g