title: Novel bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines as highly potent and selective adenosine A2A receptor antagonists.
abstract: A series of bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines was synthesized. Some of these analogues show high affinity and excellent selectivity for adenosine A(2a) receptor versus the adenosine A(1) receptor. Structure-activity-relationship (SAR) studies based on octahydropyrrolo[1,2-a]pyrazine and octahydropyrido[1,2-a]pyrazine with various capping groups are reported. Among these analogues, the most potent and selective A(2a) antagonist 26 h has a K(i) value of 0.2 nM and is 16 500-fold selective with respect to the A(1) receptor. Among a number of compounds tested, compounds 21a and 21c exhibited significantly improved metabolic stability. Compounds 21a, 21c, and 18a showed good oral efficacy in rodent catalepsy models of Parkinson's disease.
authors.affiliation: Department of Medicinal Chemistry, Biogen Idec Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. hairuo.peng@biogenidec.com
authors.forename: Hairuo
authors.initials: H
authors.lastname: Peng
authors.forename: Gnanasambandam
authors.initials: G
authors.lastname: Kumaravel
authors.forename: Gang
authors.initials: G
authors.lastname: Yao
authors.forename: Li
authors.initials: L
authors.lastname: Sha
authors.forename: Joy
authors.initials: J
authors.lastname: Wang
authors.forename: Herman
authors.initials: H
authors.lastname: Van Vlijmen
authors.forename: Tonika
authors.initials: T
authors.lastname: Bohnert
authors.forename: Carol
authors.initials: C
authors.lastname: Huang
authors.forename: Chi B
authors.initials: CB
authors.lastname: Vu
authors.forename: Carol L
authors.initials: CL
authors.lastname: Ensinger
authors.forename: Hexi
authors.initials: H
authors.lastname: Chang
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Engber
authors.forename: Eric T
authors.initials: ET
authors.lastname: Whalley
authors.forename: Russell C
authors.initials: RC
authors.lastname: Petter
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D002375:Catalepsy / Q000188:drug therapy; D004195:Disease Models, Animal; D004355:Drug Stability; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D010300:Parkinson Disease / Q000188:drug therapy; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D010879:Piperazines; D011743:Pyrimidines; D014227:Triazines; D014230:Triazoles