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.
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.
Department of Medicinal Chemistry-CV&CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Julius J
JJ
Matasi
John P
JP
Caldwell
Hongtao
H
Zhang
Ahmad
A
Fawzi
Guy A
GA
Higgins
Mary E
ME
Cohen-Williams
Geoffrey B
GB
Varty
Deen B
DB
Tulshian
D058917:Adenosine A2 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D002375:Catalepsy / Q000188:drug therapy; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
C505707:2-(2-furanyl)-7-phenyl(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D014230:Triazoles