RESUMEN
The discovery of second generation N-hydroxyurea 5-lipoxygenase inhibitors was accomplished through the development of a broad structure-activity relationship (SAR) study. This study identified requirements for improving potency and also extending duration by limiting metabolism. Potency could be maintained by the incorporation of heterocyclic templates substituted with selected lipophilic substituents. Duration of inhibition after oral administration was optimized by identification of structural features in the proximity of the N-hydroxyurea which correlated to low in vitro glucuronidation rates. Furthermore, the rate of in vitro glucuronidation was shown to be stereoselective for certain analogs. (R)-N-[3-[5-(4-Fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N-hydroxyure a (17c) was identified and selected for clinical development.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Hidroxiurea/análogos & derivados , Inhibidores de la Lipooxigenasa , Animales , Células Cultivadas , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Furanos , Glucuronatos/metabolismo , Humanos , Macaca fascicularis , Modelos Químicos , Ratas , Relación Estructura-Actividad , Moldes Genéticos , TiofenosRESUMEN
Representative examples of NSAID cyclooxygenase inhibitors such as naproxen, ibufenac, ibuprofen, and butibufen have been transformed into 5-lipoxygenase inhibitors by replacement of the carboxylic acid moiety with a 4-hydroxythiazole group.
Asunto(s)
Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Lipooxigenasa/química , Antiinflamatorios no Esteroideos/química , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Humanos , Isoenzimas/análisis , Isoenzimas/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Proteínas de la Membrana , Prostaglandina-Endoperóxido Sintasas/análisis , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Proteínas Recombinantes/análisis , Proteínas Recombinantes/antagonistas & inhibidoresRESUMEN
4-Hydroxythiazoles have been identified as potent inhibitors of 5-lipoxygenase in vitro exhibiting IC50's of less than 1 microM. An investigation of structure-activity relationships showed that the most potent inhibitors of this series are the 5-phenyl derivatives. The corresponding thiazolidin-4-one analogues were found to be relatively inactive. The 4-hydroxythiazoles were active inhibitors against 5-lipoxygenase in both intact rat polymorphonuclear leukocytes and human whole blood. The compounds were also selective inhibitors of 5-lipoxygenase, displaying only weak activity against other related enzymes, cyclooxygenase and 12- and 15-lipoxygenase.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores de la Lipooxigenasa , Tiazoles/síntesis química , Animales , Araquidonato 5-Lipooxigenasa/sangre , Fenómenos Químicos , Química , Inhibidores Enzimáticos/farmacología , Humanos , Masculino , Ratas , Ratas Endogámicas , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
3-[1-(2-Benzoxazolyl)hydrazino]propanenitrile derivatives were evaluated in the dermal and pleural reverse passive Arthus reactions in the rat. In the pleural test these compounds were effective in reducing exudate volume and accumulation of white blood cells. This pattern of activity was similar to that of hydrocortisone and different from that of indomethacin. The structural requirements for inhibiting the Arthus reactions were studied by systematic chemical modification of 1. These structure-activity relationship studies revealed that nitrogen 1' of the hydrazino group is essential for activity and must be electron rich, whereas chemical modifications of other sites of 1 had only a modest effect on activity.
Asunto(s)
Reacción de Arthus/tratamiento farmacológico , Benzoxazoles/uso terapéutico , Nitrilos/uso terapéutico , Animales , Antiinflamatorios , Benzoxazoles/síntesis química , Fenómenos Químicos , Química , Hidrazinas/síntesis química , Hidrazinas/uso terapéutico , Hidrocortisona/uso terapéutico , Enfermedades del Complejo Inmune/tratamiento farmacológico , Indometacina/uso terapéutico , Masculino , Nitrilos/síntesis química , Enfermedades Pleurales/inmunología , Ratas , Enfermedades de la Piel/inmunología , Relación Estructura-ActividadRESUMEN
A series of eicosatetraenes (2-24) were designed, synthesized, and evaluated in vitro for inhibitory activity against 5-lipoxygenase (20000g supernatant from homogenized rat basophilic leukemia cells). All compounds were found to be active with the potencies (IC50's) ranging from 0.19 to 97 microM. Compounds containing the hydroxamic acid functionality (10-12) exhibited the best activity (IC50 = 0.19-2.8 microM). The most potent inhibitor was 5-[(hydroxyamino)carbonyl]methyl]-6,8,11,14-eicosatetraenoic acid (11), which was 10 times more active than the C-1 hydroxamates of arachidonic acid or 5-HETE. Cyclization of the linear eicosanoids 2 and 14 in the C-1 to C-5 region produced compounds (21 and 24, respectively) with several-fold greater potency.
