Synthesis and SAR studies of trisubstituted purinones as potent and selective adenosine A2A receptor antagonists.
A series of trisubstituted purinones was synthesized and evaluated as A(2A) receptor antagonists. The A(2A) structure-activity relationships at the three substituted positions were studied and selectivity against the A(1) receptor was investigated. One antagonist 12o exhibits a K(i) of 9nM in an A(2A) binding assay, a K(b) of 18nM in an A(2A) cAMP functional assay, and is 220-fold selective over the A(1) receptor.
Shao
Yuefei
Y
Pharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543, USA.
Cole
Andrew G
AG
Brescia
Marc-Raleigh
MR
Qin
Lan-Ying
LY
Duo
Jingqi
J
Stauffer
Tara M
TM
Rokosz
Laura L
LL
McGuinness
Brian F
BF
Henderson
Ian
I
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011688:Purinones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D058917:Adenosine A2 Receptor Antagonists; D011688:Purinones; D043705:Receptor, Adenosine A2A; D011994:Recombinant Proteins