Biaryl and heteroaryl derivatives of SCH 58261 as potent and selective adenosine A2A receptor antagonists.
SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A(2A) receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A(2A) receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Unmesh
U
Shah
Craig D
CD
Boyle
Samuel
S
Chackalamannil
Bernard R
BR
Neustadt
Neil
N
Lindo
William J
WJ
Greenlee
Carolyn
C
Foster
Leyla
L
Arik
Ying
Y
Zhai
Kwokei
K
Ng
Shiyong
S
Wang
Angela
A
Monopoli
Jean E
JE
Lachowicz
D058917:Adenosine A2 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D008956:Models, Chemical; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy*; D010879:Piperazines / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D018696:Neuroprotective Agents; D010879:Piperazines; D011743:Pyrimidines; D011804:Quinolines; D014230:Triazoles