RESUMO
We herein report the discovery of a novel class of antagonists of the human adenosine A2B receptor. This low molecular weight scaffold has been optimized to offer derivatives with potential utility for the alleviation of conditions associated with this receptor subtype, such as nociception, diabetes, asthma and COPD. Furthermore, preliminary pharmacokinetic analysis has revealed compounds with profiles suitable for either inhaled or systemic routes of administration.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Pirimidinas/química , Administração por Inalação , Animais , Asma/tratamento farmacológico , Desenho de Fármacos , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Receptor A2A de Adenosina/metabolismo , Receptor A2B 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.