2-(2-Furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine analogs as adenosine A2A antagonists: the successful reduction of hERG activity. Part 2

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 16; pp. 3675 - 3678
• Main Authors: Matasi, Julius J, Caldwell, John P, Zhang, Hongtao, Fawzi, Ahmad, Higgins, Guy A, Cohen-Williams, Mary E, Varty, Geoffrey B, Tulshian, Deen B
• Format: Journal Article
• Language: English
• Published: England 15.08.2005
• Subjects: Adenosine A2 Receptor Antagonists; Administration, Oral; Animals; Catalepsy - drug therapy; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Molecular Structure; Motor Activity - drug effects; Pyrimidines - chemistry; Pyrimidines - classification; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology; Triazoles - therapeutic use
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.05.043

The structure-activity relationship (SAR) exploration using 2-(2-furanyl)-7-phenyl[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (1) as a template led to the identification of a novel class of potent and selective adenosine A2A receptor (AR) antagonists. However, these compounds were found to be associated with significant hERG activity. This report discusses the strategy and outcome of an expanded SAR focused on addressing the hERG liability. As a result, compounds 21 and 24 possess excellent in vitro profiles, highly promising in vivo profiles, and acceptable levels of hERG channel inhibition.