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J Med Chem ; 61(6): 2227-2245, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29457982

RESUMO

Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Preclinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclinical characterization of a potent, selective, and noncovalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Tirosina Quinase da Agamaglobulinemia/efeitos dos fármacos , Tirosina Quinase da Agamaglobulinemia/genética , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/toxicidade , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Cães , Descoberta de Drogas , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Células Madin Darby de Rim Canino , Modelos Moleculares , Estrutura Molecular , Piperazinas/farmacocinética , Piperazinas/toxicidade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/toxicidade , Piridonas/farmacocinética , Piridonas/toxicidade , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley
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