RESUMEN
Structural modification of imidazole 5-lipoxygenase (5-LO) inhibitors for optimizing inhibitory potency, pharmacokinetic behavior and toxicity (ocular) profile led to 4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]}phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (6) with no observable ocular toxicity. The orally active and safe imidazole 5-LO inhibitor 6 was selected as a clinical candidate and advanced to clinical studies. An improved synthesis of 6 is also discussed.
Asunto(s)
Imidazoles/síntesis química , Imidazoles/farmacología , Inhibidores de la Lipooxigenasa , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/farmacología , Animales , Femenino , Imidazoles/química , Imidazoles/farmacocinética , Imidazoles/toxicidad , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacocinética , Inhibidores de la Lipooxigenasa/toxicidad , Espectroscopía de Resonancia Magnética , Ratas , Ratas Sprague-DawleyRESUMEN
A convenient synthetic route to 4-[3-(4-heterocyclylphenylthio)phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide analogues as 5-LO inhibitors is described. This methodology enabled rapid development of structure-activity relationships (SARs) leading to improvement of pharmacological properties. Thus, new compounds with higher 5-LO inhibitory potency were discovered. The stereo-chemistry requirements of the tetrahydropyran ring are also discussed.
Asunto(s)
Inhibidores de la Lipooxigenasa , Inhibidores de la Lipooxigenasa/síntesis química , Piranos/síntesis química , Inhibidores de la Lipooxigenasa/farmacología , Piranos/farmacología , Relación Estructura-ActividadRESUMEN
Described herein are structure-activity relationships (SARs) of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1, CJ-12,918), an imidazole 5-lipoxygenase (5-LO) inhibitor. When 1 was tested in preclinical studies, cataract formation was observed in rats; however, this compound was metabolized extensively in vivo and showed low systemic exposure. To eliminate this side effect and enhance bioavailability, structural modification was focused on replacing the methoxy group of 1 by modulating lipophilicity (i.e., predicted log D at pH 7.4). The SARs led to the discovery of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (10, CJ-13,454), which was less lipophilic by 1.2 log D units and showed in vivo potency (ED(50) = 4-9 mg/kg) equipotent to 1. Enhanced metabolic stability resulted in fewer in vivo metabolites, as well as improved bioavailability and a better toxicological profile. Thus, 10 was found to be a more practical lead for an orally active 5-LO inhibitor.
Asunto(s)
Imidazoles/síntesis química , Inhibidores de la Lipooxigenasa , Piranos/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Catarata/inducido químicamente , Haplorrinos , Humanos , Imidazoles/farmacocinética , Imidazoles/toxicidad , Masculino , Ratones , Piranos/farmacocinética , Piranos/toxicidad , Relación Estructura-ActividadRESUMEN
Replacement of the dihydroquinolinone pharmacophore of Zeneca's ZD2138 by ionizable imidazolylphenyl moiety has lead to the discovery of a novel series of potent and orally active 5-lipoxygenase (5-LO) inhibitors. The synthesis and structure-activity relationship (SAR) of this series of compounds are described herein.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Imidazoles/síntesis química , Inhibidores de la Lipooxigenasa/síntesis química , Piranos/síntesis química , Administración Oral , Animales , Azoles/química , Azoles/farmacología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/administración & dosificación , Imidazoles/farmacología , Leucotrieno B4/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Factor de Activación Plaquetaria/antagonistas & inhibidores , Piranos/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis of 6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid (1), a selective cyclooxygenase 2 (COX-2) inhibitor, is described. The synthesis relied on a novel indole formation that involved an alkylation/1,4-addition/elimination/isomerization cascade. It was demonstrated that the entire sequence from sulfonamide 13 and bromoketone 14 to the desired indole (1) could be executed in a single pot.