RESUMEN
Soluble epoxide hydrolase (sEH, EPHX2) metabolizes eicosanoid epoxides, including epoxyeicosatrienoic acids (EETs) to the corresponding dihydroxyeicosatrienoic acids (DHETs), and leukotoxin (LTX) to leukotoxin diol (LTX diol). EETs, endothelium-derived hyperpolarizing factors, exhibit potentially beneficial properties, including anti-inflammatory effects and vasodilation. A novel, potent, selective inhibitor of recombinant human, rat and mouse sEH, GSK2256294A, exhibited potent cell-based activity, a concentration-dependent inhibition of the conversion of 14,15-EET to 14,15-DHET in human, rat and mouse whole blood in vitro, and a dose-dependent increase in the LTX/LTX diol ratio in rat plasma following oral administration. Mice receiving 10 days of cigarette smoke exposure concomitant with oral administration of GSK2256294A exhibited significant, dose-dependent reductions in pulmonary leukocytes and keratinocyte chemoattractant (KC, CXCL1) levels. Mice receiving oral administration of GSK2256294A following 10 days of cigarette smoke exposure exhibited significant reductions in pulmonary leukocytes compared to vehicle-treated mice. These data indicate that GSK2256294A attenuates cigarette smoke-induced inflammation by both inhibiting its initiation and/or maintenance and promoting its resolution. Collectively, these data indicate that GSK2256294A would be an appropriate agent to evaluate the role of sEH in clinical studies, for example in diseases where cigarette smoke is a risk factor, such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ciclohexilaminas/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Leucocitos/efectos de los fármacos , Pulmón/efectos de los fármacos , Triazinas/farmacología , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/metabolismo , Administración Oral , Adulto , Animales , Quimiocina CXCL1/biosíntesis , Relación Dosis-Respuesta a Droga , Epóxido Hidrolasas/metabolismo , Exotoxinas/metabolismo , Femenino , Humanos , Inflamación/enzimología , Inflamación/etiología , Inflamación/patología , Inflamación/prevención & control , Recuento de Leucocitos , Leucocitos/metabolismo , Leucocitos/patología , Pulmón/enzimología , Pulmón/patología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Ratas , Ácidos Esteáricos/metabolismo , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.
Asunto(s)
Antagonistas Muscarínicos/síntesis química , Tropanos/síntesis química , Animales , Enfermedades Bronquiales/tratamiento farmacológico , Diseño de Fármacos , Ratones , Antagonistas Muscarínicos/farmacología , Receptores Muscarínicos/efectos de los fármacos , Relación Estructura-Actividad , Tropanos/farmacologíaRESUMEN
The discovery of potent and selective cyanamide-based inhibitors of the cysteine protease cathepsin C is detailed. Optimization of the template with regard to plasma stability led to the identification of compound 17, a potent cathepsin C inhibitor with excellent selectivity over other cathepsins and potent in vivo activity in a cigarette smoke mouse model.