Piperazine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists.
The [1,2,4]triazolo[1,5-a]triazine derivative 3, more commonly known in the field of adenosine research as ZM-241385, has previously been demonstrated to be a potent and selective adenosine A2a receptor antagonist, although with limited oral bioavailability. This [1,2,4]triazolo[1,5-a]triazine core structure has now been improved by incorporating various piperazine derivatives. With some preliminary optimization, the A2a binding affinity of some of the best piperazine derivatives is almost as good as that of compound 3. The selectivity level over the adenosine A1 receptor subtype for some of the more active analogues is also fairly high, > 400-fold in some cases. Many compounds within this piperazine series of [1,2,4]triazolo[1,5-a]triazine have now been shown to have good oral bioavailability in the rat, with some as high as 89% (compound 35). More significantly, some piperazines derivatives of [1,2,4]triazolo[1,5-a]triazine also possessed good oral efficacy in rodent models of Parkinson's disease. For instance, compound 34 was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopamine-lesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po.
Department of Medicinal Chemistry, Biogen Idec, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142, USA. chi.vu@biogenidec.com
Chi B
CB
Vu
Bo
B
Peng
Gnanasambandam
G
Kumaravel
Glenn
G
Smits
Xiaowei
X
Jin
Deepali
D
Phadke
Thomas
T
Engber
Carol
C
Huang
Jennifer
J
Reilly
Stacy
S
Tam
Donna
D
Grant
Gregg
G
Hetu
Liqing
L
Chen
Jianbo
J
Zhang
Russell C
RC
Petter
D058917:Adenosine A2 Receptor Antagonists; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002375:Catalepsy / Q000188:drug therapy; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D020734:Parkinsonian Disorders / Q000188:drug therapy; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D013329:Structure-Activity Relationship; 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; D006574:Heterocyclic Compounds, 2-Ring; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles