RESUMO
In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA.
Assuntos
Antirreumáticos/química , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/química , Piridinas/uso terapêutico , Pirróis/química , Pirróis/uso terapêutico , Tirosina Quinase da Agamaglobulinemia , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Reumatoide/enzimologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Piridinas/farmacocinética , Piridinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
SAR studies were performed on a series of 2-arylamido-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide derivatives as cannabinoid receptor agonists. Starting from a HTS hit both potency and selectivity could be improved. Modifications to the thiophene fusion and C-3 amides were studied. A representative compound 3t produced analgesia when dosed orally in inflammatory pain models of writhing and carrageenan-induced allodynia.