RESUMO
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Desenho de Fármacos , Piridinas/farmacocinética , Quinolinas/farmacocinética , Quinolonas/farmacologia , Quinolonas/farmacocinética , Administração Oral , Proteínas Mutadas de Ataxia Telangiectasia/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Disponibilidade Biológica , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases , Piridinas/administração & dosagem , Piridinas/química , Quinolinas/administração & dosagem , Quinolinas/química , Quinolonas/administração & dosagem , Quinolonas/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This letter describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the basic group and the linker between the basic group and the phenyl central core.
Assuntos
Integrina alfa5beta1/antagonistas & inibidores , Oligopeptídeos/síntese química , Tirosina/análogos & derivados , Tirosina/síntese química , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fibrinogênio/química , Fibronectinas/química , Humanos , Integrina alfa5beta1/metabolismo , Células K562 , Modelos Moleculares , Mimetismo Molecular , Oligopeptídeos/farmacologia , Albumina Sérica/química , Relação Estrutura-Atividade , Tirosina/farmacologiaRESUMO
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This paper describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the central aromatic core and the amide moiety.
