American Chemical Society
jm701185v_si_001.pdf (1.52 MB)

2-Amino-N-pyrimidin-4-ylacetamides as A2A Receptor Antagonists: 1. Structure−Activity Relationships and Optimization of Heterocyclic Substituents

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journal contribution
posted on 2008-03-27, 00:00 authored by Deborah H. Slee, Yongsheng Chen, Xiaohu Zhang, Manisha Moorjani, Marion C. Lanier, Emily Lin, Jaimie K. Rueter, John P. Williams, Sandra M. Lechner, Stacy Markison, Siobhan Malany, Mark Santos, Raymond S. Gross, Kayvon Jalali, Yang Sai, Zhiyang Zuo, Chun Yang, Julio C. Castro-Palomino, María I. Crespo, Maria Prat, Silvia Gual, José-Luis Díaz, John Saunders
Previously we have described a novel series of potent and selective A2A receptor antagonists (e.g., 1) with excellent aqueous solubility. While these compounds are efficacious A2A antagonists in vivo, the presence of an unsubstituted furyl moiety was a cause of some concern. In order to avoid the potential metabolic liabilities that could arise from an unsubstituted furyl moiety, an optimization effort was undertaken with the aim of replacing the unsubstituted furan with a more metabolically stable group while maintaining potency and selectivity. Herein, we describe the synthesis and SAR of a range of novel heterocyclic systems and the successful identification of a replacement for the unsubstituted furan moiety with a methylfuran or thiazole moiety while maintaining potency and selectivity.