RESUMEN
The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.
Asunto(s)
Aldehído Oxidasa/metabolismo , Inhibidores de las Cinasas Janus/farmacocinética , Pulmón/metabolismo , Administración Intranasal , Administración Intravenosa , Animales , Sitios de Unión , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/síntesis química , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Simulación del Acoplamiento Molecular , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of potent quinoline-based human H1 and H3 bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1 potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1vs 6.8 for azelastine), better selectivity over α1A, α1B and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.
