N-[6-Amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A(2A) Receptor Antagonists with Improved Drug Like Properties and in Vivo Efficacy

作者：Lanier Marion C; Moorjani Manisha; Luo Zhiyong; Chen Yongsheng; Lin Emily; Tellew John E; Zhang Xiaohu; Williams John P; Gross Raymond S; Lechner Sandra M; Markison Stacy; Joswig Tanya; Kargo William; Piercey Jaime; Santos Mark; Malany Siobhan; Zhao Marilyn; Petroski Robert; Crespo Maria I; Diaz Jose Luis; Saunders John; Wen Jenny; O'Brien Zhihong; Jalali Kayvon; Madan Ajay; Slee Deborah H^*

来源：Journal of Medicinal Chemistry, 2009, 52(3): 709-717.

DOI：10.1021/jm800908d

In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA(2A)) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R-1 is an aromatic heterocycle, R-2 is a short-chain alkyl amide, and the typical R-3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.

• 出版日期2009-2-12