2-Amino-N-pyrimidin-4-ylacetamides as A2A Receptor Antagonists: 2. Reduction of hERG Activity, Observed Species Selectivity, and Structure−Activity Relationships

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• 作者：Deborah H. Slee ; Manisha Moorjani ; Xiaohu Zhang ; Emily Lin ; Marion C. Lanier ; Yongsheng Chen ; Jaimie K. Rueter ; Sandra M. Lechner ; Stacy Markison ; Siobhan Malany ; Tanya Joswig ; Mark Santos ; Raymond S.
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 27, 2008
• 年：2008
• 卷：51
• 期：6
• 页码：1730 - 1739
• 全文大小：303K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

Previously we have described a series of novel A_2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A_2A vs the human A₁ receptor, and minimize activity against the hERG channel. In addition, the observed structure−activity relationships against both the human and the rat A_2A receptor are reported.