RESUMEN
Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Proteínas Portadoras/antagonistas & inhibidores , Indoles/farmacología , Inflamación/tratamiento farmacológico , Proteínas de la Membrana/antagonistas & inhibidores , Propionatos/farmacología , Proteínas Activadoras de la 5-Lipooxigenasa , Enfermedad Aguda , Administración Oral , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Asma/tratamiento farmacológico , Asma/enzimología , Asma/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Extravasación de Materiales Terapéuticos y Diagnósticos/tratamiento farmacológico , Extravasación de Materiales Terapéuticos y Diagnósticos/enzimología , Extravasación de Materiales Terapéuticos y Diagnósticos/metabolismo , Femenino , Humanos , Indoles/uso terapéutico , Inflamación/enzimología , Inflamación/metabolismo , Leucotrieno B4/biosíntesis , Leucotrieno B4/sangre , Masculino , Ratones , Ratones Endogámicos BALB C , Neumonía/tratamiento farmacológico , Neumonía/enzimología , Neumonía/metabolismo , Propionatos/uso terapéutico , Ratas , Ratas Sprague-Dawley , ZimosanRESUMEN
The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vivo activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC(50) of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC(50) of 349 nM in the human blood LTB(4) inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase 1 trials in healthy volunteers.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Indoles/farmacocinética , Leucotrieno B4/antagonistas & inhibidores , Proteínas de la Membrana/antagonistas & inhibidores , Propionatos/farmacocinética , Proteínas Activadoras de la 5-Lipooxigenasa , Animales , Asma/tratamiento farmacológico , Perros , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Compuestos Heterocíclicos/química , Humanos , Concentración 50 Inhibidora , Leucotrieno B4/biosíntesis , Ratones , Unión Proteica , Ratas , Relación Estructura-ActividadRESUMEN
The SAR of the lead compound 3, a novel ligand for the alpha(2)delta subunit of voltage-gated calcium channels, was rapidly explored. Utilizing a parallel solution-phase Sn2Ar coupling approach, a focused library was obtained. The library was evaluated in vitro and afforded a series of analogues with improved potencies. The SAR trends of the library are also described.
Asunto(s)
Canales de Calcio/metabolismo , Técnicas Químicas Combinatorias/métodos , Activación del Canal Iónico , Subunidades de Proteína/metabolismo , Canales de Calcio/química , Canales de Calcio/efectos de los fármacos , Humanos , Ligandos , Subunidades de Proteína/química , Soluciones/química , Relación Estructura-ActividadRESUMEN
A novel class of 6-aryl-6H-pyrrolo[3,4-d]pyridazine ligands for the alpha2delta subunit of voltage-gated calcium channels has been described. Substitutions in the aryl ring of the molecule were generally not tolerated, and resulted in diminished binding to the alpha2delta subunit. Modifications to the pyridazine ring revealed numerous permissive substitutions, and detailed SAR studies were carried out in this portion of the molecule. Replacement of the pyridazine ring methyl group with an aminomethyl functionality provided greatly improved potency over the initial lead. The initial lead compound displayed good rat pharmacokinetic properties, and was shown to be efficacious in the Chung model for neuropathic pain in rats.
Asunto(s)
Canales de Calcio/metabolismo , Subunidades de Proteína/metabolismo , Piridazinas/síntesis química , Piridazinas/metabolismo , Animales , Evaluación Preclínica de Medicamentos/métodos , Ligandos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , RatasRESUMEN
A novel class of 2H-pyrrolo[3,4-c]pyridazine ligands of the alpha (2) delta subunit of voltage-gated calcium channels is described. Compound 4a with high affinity toward alpha (2) delta was identified through structure-activity relationship studies of the lead compound. Tritiated ligand [(3)H]-4b was synthesized to demonstrate that this ligand binds to the same site as Gabapentin toward alpha (2) delta subunit of voltage-gated calcium channels.