RESUMEN
AIM: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations. METHOD: Western European subjects received single (50-1000 mg) or multiple (10-450 mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10-200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B4 and leukotriene E4, respectively, as pharmacodynamic markers of drug activity. RESULTS: There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16-34 h. Dose-dependent inhibition of blood leukotriene B4 production was observed and near complete inhibition of urinary leukotriene E4 excretion was shown at all doses except the lowest dose. The EC50 values for inhibition of LTB4 were 85 nM and 89 nM in the Western European and Japanese studies, respectively. CONCLUSION: GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E4 at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB4.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa , Indoles , Leucotrieno E4/sangre , Ácidos Pentanoicos , Inhibidores de Proteína Activante de 5-Lipoxigenasa/efectos adversos , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Administración Oral , Adolescente , Adulto , Anciano , Área Bajo la Curva , Pueblo Asiatico , Biomarcadores/sangre , Biomarcadores/orina , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Indoles/farmacología , Leucotrieno B4/sangre , Leucotrieno B4/orina , Leucotrieno E4/orina , Masculino , Persona de Mediana Edad , Ácidos Pentanoicos/efectos adversos , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacología , Población Blanca , Adulto JovenRESUMEN
A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/síntesis química , Proteínas Activadoras de la 5-Lipooxigenasa/química , Alcanos/síntesis química , Antialérgicos/síntesis química , Derivados del Benceno/síntesis química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Alcanos/farmacocinética , Alcanos/farmacología , Animales , Antialérgicos/farmacocinética , Antialérgicos/farmacología , Derivados del Benceno/farmacocinética , Derivados del Benceno/farmacología , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
AZD5718 is a first-in-class small-molecule anti-inflammatory drug with the potential to reduce the residual risk of cardiovascular events after myocardial infarction in patients receiving lipid-lowering statin therapy. Leukotrienes are potent proinflammatory and vasoactive mediators synthesized in leukocytes via 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP). AZD5718 is a FLAP inhibitor that dose-dependently reduced leukotriene biosynthesis in a first-in-human study. We enrolled 12 healthy men in a randomized, open-label, crossover, single-dose phase 1 pharmacokinetic study of AZD5718 to investigate a potential drug-drug interaction with rosuvastatin, and the effects of formulation and food intake (ClinicalTrials.gov identifier: NCT02963116). Rosuvastatin (10 mg) were absorbed more rapidly when coadministered with AZD5718 (200 mg), probably owing to weak inhibition of hepatic statin uptake, but relative bioavailability was unaffected (geometric least-squares mean ratio [GMR], 100%; 90% confidence interval [CI], 86%-116%). AZD5718 pharmacokinetics were unaffected by coadministration of rosuvastatin. AZD5718 (200 mg) was absorbed less rapidly when formulated as tablets than oral suspension, with reduced relative bioavailability (GMR, 72%; 90%CI, 64%-80%). AZD5718 absorption was slower when 200-mg tablets were taken after a high-fat breakfast than after fasting, but relative bioavailability was unaffected (GMR, 96%; 90%CI, 87%-106%). In post hoc pharmacodynamic simulations, plasma leukotriene B4 levels were inhibited by >90% throughout the day following once-daily AZD5718, regardless of formulation or administration with food. AZD5718 was well tolerated, with no severe or serious adverse events. These data supported the design of a phase 2a efficacy study of AZD5718 in patients with coronary artery disease.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Interacciones Alimento-Droga , Pirazoles/farmacocinética , Rosuvastatina Cálcica/farmacología , Inhibidores de Proteína Activante de 5-Lipoxigenasa/administración & dosificación , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Administración Oral , Adulto , Disponibilidad Biológica , Estudios Cruzados , Interacciones Farmacológicas , Ayuno , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Persona de Mediana Edad , Pirazoles/administración & dosificación , Pirazoles/farmacología , Rosuvastatina Cálcica/administración & dosificación , Adulto JovenRESUMEN
5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments while balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing. The superior safety profile of AZD5718 compared to earlier frontrunner compounds allowed us to perform a phase 1 clinical study in which AZD5718 demonstrated a dose dependent and greater than 90% suppression of leukotriene production over 24 h. Currently, AZD5718 is evaluated in a phase 2a study for treatment of coronary artery disease.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/uso terapéutico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Pirazoles/uso terapéutico , Inhibidores de Proteína Activante de 5-Lipoxigenasa/química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Animales , Línea Celular Tumoral , Ensayos Clínicos Fase I como Asunto , Perros , Descubrimiento de Drogas , Femenino , Humanos , Leucotrieno B4/antagonistas & inhibidores , Masculino , Estructura Molecular , Pirazoles/química , Pirazoles/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem.2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett.2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB(4) inhibition with longer drug preincubation times (15 min vs 5 h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC(50) of 76 nM for inhibition of LTB(4) in human blood (5 h incubation) and excellent preclinical toxicology and pharmacokinetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients.