RESUMO
Potent and selective antagonists of the adenosine A2A receptor often contain a nitrogen-rich fused-ring heterocyclic core. Replacement of the core with an isomeric ring system has previously been shown to improve target affinity, selectivity, and in vivo activity. This paper describes the preparation, by a novel route, of A2A receptor antagonists containing the [1,2,4]triazolo[1,5-a]pyrazine nucleus, which is isomeric with the [1,2,4]triazolo[1,5-c]pyrimidine core of a series of known A2A antagonists with in vivo activity in animal models of Parkinson's disease.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Pirazinas/síntese química , Animais , Encéfalo/ultraestrutura , Membrana Celular/química , Membrana Celular/metabolismo , Modelos Animais de Doenças , Doença de Parkinson/tratamento farmacológico , Pirazinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antiparkinsonianos/síntese química , Diaminas/síntese química , Pirrolidinas/síntese química , Triazinas/síntese química , Triazóis/síntese química , Administração Oral , Animais , Antiparkinsonianos/química , Antiparkinsonianos/farmacologia , Ligação Competitiva , Disponibilidade Biológica , Catalepsia/tratamento farmacológico , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Técnicas de Química Combinatória , Diaminas/química , Diaminas/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Pirrolidinas/química , Pirrolidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Triazinas/química , Triazinas/farmacologia , Triazóis/química , Triazóis/farmacologiaRESUMO
Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been shown to be potent and selective adenosine A(2a) receptor antagonists. We now demonstrate that potent and selective A(2a) receptor antagonists could still be obtained when the arylpiperazines are separated from the triazolotriazine core structure by an ethylenediamine spacer. Selected analogs bearing this triazolotriazine or the related triazolopyrimidine core structure have been found to be orally active in a mouse catalepsy model of Parkinson's disease.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antiparkinsonianos/síntese química , Animais , Antiparkinsonianos/farmacologia , Camundongos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacologia , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
Piperazine and (R)-2-(aminomethyl)pyrrolidine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been shown to be potent and selective adenosine A(2a) receptor antagonists. We have replaced the triazolotriazine core structure with two different heterocyclic cores. One of these, the one deriving from [1,2,4]triazolo[1,5-c]pyrimidine, appears to be particularly effective and selected analogs from this series have been shown to be orally active in a mouse catalepsy model of Parkinson's disease.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antiparkinsonianos/farmacologia , Animais , Catalepsia/tratamento farmacológico , Camundongos , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
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.
