RESUMO
A novel series of antagonists of the human A(2A) receptor have been identified and have been shown to display good potency and high degrees of selectivity over other receptor sub-types. Displaying in vivo potency in commonly used disease models and high oral bio-availability, this class of compounds may serve as clinically useful treatments for the relief of the symptoms associated with Parkinson's disease.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Amidas/síntese química , Pirimidinas/química , Administração Oral , Amidas/administração & dosagem , Amidas/química , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Receptor A2A de Adenosina/metabolismoRESUMO
Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Doença de Parkinson/tratamento farmacológico , Pirimidinas/química , Pirimidinas/farmacologia , Receptor A2A de Adenosina/metabolismo , Animais , Humanos , Locomoção/efeitos dos fármacos , Camundongos , Ligação Proteica , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
A series of pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and 6-arylpurine adenosine A(2A) antagonists is described. Many examples were highly selective against the human A(1) receptor sub-type and were active in an in vivo model of Parkinson's disease.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antiparkinsonianos/uso terapêutico , Desenho de Fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Antagonistas do Receptor A1 de Adenosina , Antiparkinsonianos/síntese química , Humanos , Modelos Químicos , Purinas/síntese química , Pirazóis/síntese química , Pirimidinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We describe herein the discovery and development of a series of 4-arylthieno[3,2-d]pyrimidines which are potent adenosine A(2A) receptor antagonists. These novel compounds show high degrees of selectivity against the human A(1), A(2B) and A(3) receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antiparkinsonianos/uso terapêutico , Desenho de Fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Pirimidinas/uso terapêutico , Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A3 de Adenosina , Antiparkinsonianos/síntese química , Humanos , Modelos Químicos , Pirimidinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antimaláricos/uso terapêutico , Antiparkinsonianos/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Pirimidinas/uso terapêutico , Antimaláricos/síntese química , Antiparkinsonianos/síntese química , Humanos , Modelos Químicos , Pirimidinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Azóis/síntese química , Azóis/farmacologia , Desenho de Fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Aminas/química , Animais , Azóis/química , Azóis/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Transtornos Neurológicos da Marcha/induzido quimicamente , Transtornos Neurológicos da Marcha/tratamento farmacológico , Haloperidol/farmacologia , Humanos , Camundongos , Estrutura Molecular , Pirimidinas/química , Pirimidinas/uso terapêutico , Ratos , Receptor A2A de Adenosina/classificação , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
Water soluble prodrugs of hybrid free radical scavenger/iron chelating molecules, based on 3,5-disubstituted-4-hydroxyphenyl derivatives and 3-hydroxy-2-methyl-4(1H)-pyridinone (deferiprone), have been prepared. Related hybrid molecules containing a covalent poly(ethylene)glycol or an amine linker were also synthesized.