RESUMO
The discovery of potent small molecule dual antagonists of the human CCR3 and H(1) receptors is described for the treatment of allergic diseases, for example, asthma and allergic rhinitis. Optimizing in vitro potency and metabolic stability, starting from a CCR1 lead compound, led to compound 20 with potent dual CCR3/H(1) activity and in vitro metabolic stability.
Assuntos
Descoberta de Drogas , Ácidos Hidroxâmicos/farmacologia , Piperidinas/farmacologia , Receptores CCR3/antagonistas & inibidores , Receptores Histamínicos H1/metabolismo , Animais , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/metabolismo , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Ratos , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic profile.
Assuntos
Descoberta de Drogas , Piperidinas/farmacologia , Receptores CCR3/antagonistas & inibidores , Receptores Histamínicos H1/metabolismo , Animais , Cães , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Ratos , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
A novel series of antagonists of the human P2X7 receptor is described. Modification of substituents enabled identification of compounds selective for the rat P2X7 receptor and provides useful pharmacological tools for evaluation of the role of P2X7 in disease.