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 series of dual CCR3/H(1) antagonists based on a bispiperidine scaffold were discovered. Introduction of an acidic group overcame hERG liability. Bioavailability was optimised by modulation of physico-chemical properties and physical form to deliver a compound suitable for clinical evaluation.
Assuntos
Descoberta de Drogas , Antagonistas dos Receptores Histamínicos H1/química , Receptores CCR3/antagonistas & inibidores , Animais , Interações Medicamentosas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Estrutura Molecular , Piperidinas/química , Ratos , Fatores de RiscoRESUMO
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
