Piperazine derivatives of [1,2,4]triazolo[1,5-alpha][1,3,5]triazine as potent and selective adenosine A(2a) receptor antagonists

• Published in: Journal of medicinal chemistry Vol. 47; no. 17; pp. 4291 - 4299
• Main Authors: Vu, CB, Peng, B, Kumaravel, G, Smits, G, Jin, XW, Phadke, D, Engber, T, Huang, C, Reilly, J, Tam, S, Grant, D, Hetu, G, Chen, LQ, Zhang, JB, Petter, RC
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 12.08.2004
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; CVT-124; LOCALIZATION; RAT; CATALEPSY; ZM241385; MPTP; MONKEYS; EXPRESSION; AGONISTS; PARKINSONS-DISEASE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0498405

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 A(2a) 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 A, 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.