Antagonists of the Human A2A Adenosine Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines

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• 作者：Roger J. Gillespie ; Samantha J. Bamford ; Ruth Botting ; Mike Comer ; Sarah Denny ; Suneel Gaur ; Michael Griffin ; Allan M. Jordan ; Anthony R. Knight ; Joanne Lerpiniere ; Stefania Leonardi ; Sean Lightowler
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：January 8, 2009
• 年：2009
• 卷：52
• 期：1
• 页码：33-47
• 全文大小：303K
• 年卷期：v.52,no.1(January 8, 2009)
• ISSN：1520-4804

文摘

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.