title: Novel diamino derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists.
abstract: Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been demonstrated to be potent and selective adenosine A(2a) receptor antagonists with oral activity in rodent models of Parkinson's disease. We have replaced the piperazinyl group with a variety of linear, monocyclic, and bicyclic diamines. Of these diamines, (R)-2-(aminomethyl)pyrrolidine is a particularly potent and selective replacement for the piperazinyl group. With this diamine component, we have been able to prepare numerous analogues with low nanomolar affinity toward the A(2a) receptor and good selectivity with respect to the A(1) receptor (>200-fold in some cases). Selected analogues from this series of [1,2,4]triazolo[1,5-a][1,3,5]triazine have now been shown to be orally active in the mouse catalepsy model.
authors.affiliation: Department of Medicinal Chemistry, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. chi.vu@biogenidec.com
authors.forename: Chi B
authors.initials: CB
authors.lastname: Vu
authors.forename: Deborah
authors.initials: D
authors.lastname: Pan
authors.forename: Bo
authors.initials: B
authors.lastname: Peng
authors.forename: Gnanasambandam
authors.initials: G
authors.lastname: Kumaravel
authors.forename: Glenn
authors.initials: G
authors.lastname: Smits
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Jin
authors.forename: Deepali
authors.initials: D
authors.lastname: Phadke
authors.forename: Thomas
authors.initials: T
authors.lastname: Engber
authors.forename: Carol
authors.initials: C
authors.lastname: Huang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reilly
authors.forename: Stacy
authors.initials: S
authors.lastname: Tam
authors.forename: Donna
authors.initials: D
authors.lastname: Grant
authors.forename: Gregg
authors.initials: G
authors.lastname: Hetu
authors.forename: Russell C
authors.initials: RC
authors.lastname: Petter
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001682:Biological Availability; D002375:Catalepsy / Q000188:drug therapy; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; 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; D000978:Antiparkinson Agents; D003959:Diamines; D011759:Pyrrolidines; D014227:Triazines; D014230:Triazoles