Discovery of 1,2,4-Triazine Derivatives as Adenosine A2A Antagonists using Structure Based Drug Design

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• 作者：Miles Congreve ; Stephen P. Andrews ; Andrew S. Dor茅 ; Kaspar Hollenstein ; Edward Hurrell ; Christopher J. Langmead ; Jonathan S. Mason ; Irene W. Ng ; Benjamin Tehan ; Andrei Zhukov ; Malcolm Weir ; Fiona H. Marshall
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：1898-1903
• 全文大小：291K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

Potent, ligand efficient, selective, and orally efficacious 1,2,4-triazine derivatives have been identified using structure based drug design approaches as antagonists of the adenosine A_2A receptor. The X-ray crystal structures of compounds 4e and 4g bound to the GPCR illustrate that the molecules bind deeply inside the orthosteric binding cavity. In vivo pharmacokinetic and efficacy data for compound 4k are presented, demonstrating the potential of this series of compounds for the treatment of Parkinson鈥檚 disease.