N-[6-Amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A2A Receptor Antagonists with Improved Drug Like Properties and in Vivo Efficacy

• Published in: Journal of medicinal chemistry 2009-02, Vol.52 (3), p.709-717
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - therapeutic use; Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Animals; Behavior, Animal - drug effects; Catalepsy - chemically induced; Catalepsy - drug therapy; Drug Synergism; Haloperidol; Humans; Pyrimidines - chemical synthesis; Pyrimidines - therapeutic use; Rats; Rotation; Solubility; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• 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.