Antagonists of the Human A2A Adenosine Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines
Antagonists of the Human A2A Adenosine Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines
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DOI：
10.1021/jm800961g
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发表时间：
2009-01-08
影响因子：
7.3
通讯作者：
Weiss, Scott M.
中科院分区：
文献类型：
--
作者：
Gillespie, Roger J.;Bamford, Samantha J.;Weiss, Scott M.
人A（2A）受体的拮抗作用已被认为是缓解与帕金森病相关的症状的治疗干预点。这被认为至少部分是通过增加多巴胺能神经元对残留的、耗尽的纹状体多巴胺水平的敏感性而发生的。我们在此描述了一系列新的功能化的三唑并[4，5-d]嘧啶衍生物，其显示A2 A受体的功能性拮抗作用。这些化合物的优化导致了关键衍生物的效力、选择性和药代动力学性质的改善。这些努力导致了60（V2006/BIIB 014）的发现，其在常用的帕金森病模型中显示出强的口服活性。此外，该衍生物已显示出优异的临床前药代动力学，并已成功完成I期临床研究。该化合物目前正在与Biogen Idec合作进行进一步的临床评价。
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 A2A 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.