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
The SAR of a series of novel pyrido[3,4-d]pyramid-4-ylamine mGluR1 antagonists is described. The multiple of the unbound K(i) in cerebrospinal fluid necessary to give morphine like analgesic effects in an electromyograph pinch model in rodents is determined and the effect of structure on CNS penetration examined.
Assuntos
Antagonistas de Aminoácidos Excitatórios/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Eletromiografia/métodos , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Receptores de Glutamato Metabotrópico/fisiologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Agonistas do Receptor A2 de Adenosina , Adenosina/análogos & derivados , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Adenosina/farmacocinética , Adenosina/farmacologia , Administração por Inalação , Administração Oral , Aminas/farmacocinética , Aminas/farmacologia , Animais , Cobaias , Humanos , Pulmão/metabolismo , Fenetilaminas/farmacocinética , Fenetilaminas/farmacologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
A series of novel mGluR1 antagonists have been prepared. Incorporation of fragments derived from weak lead matter into a library led to enhanced potency in a new chemical series. A chemistry driven second library iteration, covering a greatly enhanced area of chemical space, maintained good potency and introduced metabolic stability.
