title: Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines.
abstract: 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.
authors.affiliation: Department of Chemical Research, , Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. bernard.neustadt@spcorp.com
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Neustadt
authors.forename: Jinsong
authors.initials: J
authors.lastname: Hao
authors.forename: Neil
authors.initials: N
authors.lastname: Lindo
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stamford
authors.forename: Deen
authors.initials: D
authors.lastname: Tulshian
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
authors.forename: John
authors.initials: J
authors.lastname: Hunter
authors.forename: Angela
authors.initials: A
authors.lastname: Monopoli
authors.forename: Rosalia
authors.initials: R
authors.lastname: Bertorelli
authors.forename: Carolyn
authors.initials: C
authors.lastname: Foster
authors.forename: Leyla
authors.initials: L
authors.lastname: Arik
authors.forename: Jean
authors.initials: J
authors.lastname: Lachowicz
authors.forename: Kwokei
authors.initials: K
authors.lastname: Ng
authors.forename: Kung-I
authors.initials: KI
authors.lastname: Feng
mesh_terms: 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
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D010879:Piperazines; D011743:Pyrimidines; D000077489:Piperazine