RESUMEN
The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.
Asunto(s)
Alérgenos/inmunología , Asma/tratamiento farmacológico , Asma/inmunología , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/antagonistas & inhibidores , Nitrilos/farmacología , Fosfoproteínas/metabolismo , Piperidinas/farmacología , Pirimidinas/farmacología , Factores de Transcripción STAT/metabolismo , Administración por Inhalación , Animales , Asma/metabolismo , Asma/patología , Inflamación/tratamiento farmacológico , Isoenzimas/antagonistas & inhibidores , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/farmacocinética , Inhibidores de las Cinasas Janus/uso terapéutico , Masculino , Nitrilos/administración & dosificación , Nitrilos/farmacocinética , Nitrilos/uso terapéutico , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.
Asunto(s)
Imidazoles/química , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/antagonistas & inhibidores , Piridinas/química , Piridonas/química , Enfermedades Respiratorias/tratamiento farmacológico , Administración por Inhalación , Animales , Humanos , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/química , Inhibidores de las Cinasas Janus/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ratas , Relación Estructura-ActividadRESUMEN
A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/síntesis química , Indoles/síntesis química , Piperidinas/síntesis química , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Electrocardiografía/efectos de los fármacos , Cobayas , Semivida , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores Histamínicos H1/toxicidad , Humanos , Técnicas In Vitro , Indoles/farmacología , Indoles/toxicidad , Masculino , Ratones , Piperidinas/farmacología , Piperidinas/toxicidad , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Histamínicos H1/efectos de los fármacos , Receptores Histamínicos H1/metabolismo , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Piel/irrigación sanguínea , Relación Estructura-ActividadRESUMEN
The preparation of the sulfoxide analogues 7, 8, and 9 and their enantiomerically pure forms is discussed as well as their ability to act as prodrugs of the potent and selective sulfone-containing COX-2 inhibitors 1, 2, and 3. Sulfoxide derivatives 7 and 9 were shown to be rapidly transformed in vivo into the corresponding sulfone derivatives 1 and 3, after oral administration to rats.