RESUMO
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
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
Ligand-based virtual screening led to the discovery of a new class of potent inverse agonists of the human cannabinoid receptor 1, hCB(1), which are selective versus hCB(2). These CB(1) ligands present intriguing departures from a classical CB(1) antagonist pharmacophore. Elements of SAR are discussed in this context.
