RESUMEN
Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Descubrimiento de Drogas , Enfermedades del Sistema Inmune/tratamiento farmacológico , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Administración Oral , Agammaglobulinemia Tirosina Quinasa/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Enfermedades del Sistema Inmune/metabolismo , Estructura Molecular , Piperidinas/administración & dosificación , Piperidinas/química , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Recently developed copper-catalyzed coupling methodology has been applied to the synthesis of amino acid derived enamides. Bond formation proved to be strongly influenced by protection strategy and vinyl iodide substitution while tolerant of limited side chain functionality. Assessment of aminopeptidase activity revealed a preference for (E)-1,2-disubstituted constructs.