Novel diamino derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists.
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.
Vu
Chi B
CB
Department of Medicinal Chemistry, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. chi.vu@biogenidec.com
Pan
Deborah
D
Peng
Bo
B
Kumaravel
Gnanasambandam
G
Smits
Glenn
G
Jin
Xiaowei
X
Phadke
Deepali
D
Engber
Thomas
T
Huang
Carol
C
Reilly
Jennifer
J
Tam
Stacy
S
Grant
Donna
D
Hetu
Gregg
G
Petter
Russell C
RC
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
D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D003959:Diamines; D011759:Pyrrolidines; D014227:Triazines; D014230:Triazoles