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 María I, Díaz José-Luis, Saunders John, Wen Jenny, O'Brien Zhihong, Jalali Kayvon, Madan Ajay, Slee Deborah H
Department of Medicinal Chemistry, Neurocrine Biosciences, 12780 El Camino Real, San Diego, California 92130, USA.
J Med Chem. 2009 Feb 12;52(3):709-17. 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 (hA2A) 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 R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 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.
在本文中，我们报道了一种改善一系列小分子人腺苷2A（hA2A）拮抗剂物理性质的策略。该系列拮抗剂典型的一个芳香环被一系列脂肪族基团取代，目的是破坏分子的晶体堆积以降低熔点，进而提高溶解度。在此，我们描述了一系列新型水溶性2,4,6-三取代嘧啶的构效关系，其中R1是一个芳香杂环，R2是一个短链烷基酰胺，并且典型的R3芳香杂环取代基被一个脂肪族氨基取代基所取代。这种方法显著提高了水溶性并降低了该体系的脂水分配系数，从而提供了没有明显hERG或CYP相关问题且具有强大体内疗效的分子。
