RESUMEN
Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
Asunto(s)
Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , RatasRESUMEN
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Isoquinolinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/metabolismo , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/metabolismoRESUMEN
The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Ciclopropanos/síntesis química , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Pirazinas/síntesis química , Pirroles/síntesis química , Administración Oral , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Células CACO-2 , Cristalografía por Rayos X , Ciclopropanos/farmacocinética , Ciclopropanos/farmacología , Técnicas de Silenciamiento del Gen , Ensayos Analíticos de Alto Rendimiento , Humanos , Interleucina-2/fisiología , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , Janus Quinasa 3/genética , Janus Quinasa 3/metabolismo , Ratones , Modelos Moleculares , Pirazinas/farmacocinética , Pirazinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , ARN Interferente Pequeño/genética , Ratas , Receptores de Interleucina-6/fisiología , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.