Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines.
Antagonism of the adenosine A2A receptor offers great promise in the treatment of Parkinson's disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.
Neustadt
Bernard R
BR
Department of Chemical Research, , Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. bernard.neustadt@spcorp.com
Hao
Jinsong
J
Lindo
Neil
N
Greenlee
William J
WJ
Stamford
Andrew W
AW
Tulshian
Deen
D
Ongini
Ennio
E
Hunter
John
J
Monopoli
Angela
A
Bertorelli
Rosalia
R
Foster
Carolyn
C
Arik
Leyla
L
Lachowicz
Jean
J
Ng
Kwokei
K
Feng
Kung-I
KI
D058917:Adenosine A2 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D010300:Parkinson Disease / Q000188:drug therapy; D000077489:Piperazine; D010879:Piperazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D016896:Treatment Outcome
D058917:Adenosine A2 Receptor Antagonists; D010879:Piperazines; D011743:Pyrimidines; D000077489:Piperazine