RESUMO
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. The pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists is described leading through to human pharmacokinetic data for a clinical candidate.
Assuntos
Agonistas do Receptor A2 de Adenosina , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Adenosina/análogos & derivados , Adenosina/química , Administração por Inalação , Adolescente , Adulto , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Pulmão/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Modelos Químicos , Fenetilaminas/química , Purinas/química , Ratos , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
COPD is a major cause of mortality in the western world. A(2A) agonists are postulated to reduce the lung inflammation that causes COPD. The cardiovascular effects of A(2A) agonists dictate that a compound needs to be delivered by inhalation to be therapeutically useful. A strategy of minimizing side-effect liability by maximizing systemic clearance was followed and pharmacological and pharmacokinetic SAR of a series of inhaled A(2A) agonists described. A sevenfold improvement in potency and 150-fold reduction in side-effect liability over the lead compound CGS-21680, were obtained.