RESUMEN
Tyrosine kinase 2 (TYK2) is a nonreceptor tyrosine kinase that belongs to the JAK family also comprising JAK1, JAK2, and JAK3. TYK2 is an attractive target for various autoimmune diseases as it regulates signal transduction downstream of IL-23 and IL-12 receptors. Selective TYK2 inhibition offers a differentiated clinical profile compared to currently approved JAK inhibitors. However, selectivity for TYK2 versus other JAK family members has been difficult to achieve with small molecules that inhibit the catalytically active kinase domain. Successful targeting of the TYK2 pseudokinase domain as a strategy to achieve isoform selectivity was recently exemplified with deucravacitinib. Described herein is the optimization of selective TYK2 inhibitors targeting the pseudokinase domain, resulting in the discovery of the clinical candidate ABBV-712 (21).
Asunto(s)
Enfermedades Autoinmunes , TYK2 Quinasa , Humanos , Quinasas JanusRESUMEN
Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2.
Asunto(s)
Janus Quinasa 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Triazoles/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Janus Quinasa 1/metabolismo , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazinas/síntesis química , Pirazinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
Interest in therapeutic kinase inhibitors continues to grow beyond success in oncology. To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine. Herein we describe the syntheses of eight alternative tricyclic cores as well as in vitro screening results for representative kinases of potential therapeutic interest.