RESUMEN
The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Activados por la Liberación de Calcio/antagonistas & inhibidores , Calcio/metabolismo , Descubrimiento de Drogas , Administración Oral , Animales , Área Bajo la Curva , Artritis Reumatoide/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/farmacocinética , Ensayos Clínicos Fase I como Asunto , Humanos , Células Jurkat , Masculino , Ratones , Ratones Endogámicos BALB C , Ratas , Ratas Endogámicas Lew , Relación Estructura-ActividadRESUMEN
The sensitivity of the various preclinical models used to predict toxicity in humans varies. In this review, we analyze the various models used to predict safety in drug discovery and development with a view to understanding their translational value in humans. Twenty recently approved anticancer drugs were studied and the available nonclinical and clinical adverse effects information available from the US Food and Drug Administration (FDA) was analyzed. We found that gastrointestinal and hematopoietic toxicities in humans were predicted to the maximum extent by nonclinical models, whereas respiratory, integumentary, renal, nervous, hepatic, and cardiovascular were moderately predicted. Ocular, endocrine, and musculoskeletal toxicities were poorly predicted while lymphatic and immune toxicities were difficult to predict.