Identification of Novel, Water-Soluble, 2-Amino-N-pyrimidin-4-yl Acetamides as A2A Receptor Antagonists with In Vivo Efficacy

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• 作者：Deborah H. Slee ; Xiaohu Zhang ; Manisha Moorjani ; 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：February 14, 2008
• 年：2008
• 卷：51
• 期：3
• 页码：400 - 406
• 全文大小：217K
• 年卷期：v.51,no.3(February 14, 2008)
• ISSN：1520-4804

文摘

Potent adenosine hA_2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure–activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA_2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson’s disease, despite having reduced potency for the rat A_2A receptor versus the human A_2A receptor.