RESUMEN
The structural requirements for inhibition of RBL-1 (rat basophilic leukemia) 5-lipoxygenase by 15-hydroxyeicosa-5,8,11,13-tetraenoic acid (15-HETE, 1) were studied by systematic chemical modifications of the molecule at the hydroxyl and carboxyl groups, the double bonds, and the carboxylate and omega side chains. The most potent inhibitors were analogues that contained a 5,8-cis,cis-diene system and acted as alternate substrates for the enzyme. However, several analogues in which the 5,8-diene had been reduced were also found to inhibit the enzyme. Inhibition of 5-lipoxygenase by 15-hydroxyeicosa-11,13-dienoic acid (15-HEDE) analogues was optimal in compounds that generally contained a free carboxyl group, a carboxylate side chain of nine carbons, an omega side chain of five or six carbons, a cis,trans- or trans,cis-11,13-diene or 11,13-diyne system, and a 15-hydroxyl group. Conversion of 15-HEDE to its 16-membered lactone reduced but did not eliminate 5-lipoxygenase inhibitory activity. In contrast, a 3- to 10-fold enhancement of activity occurred when 5,15-diHETE (58) or 5-HETE (56) were cyclized to their respective delta-lactones. Molecular modeling of 15-HEDE analogues, modified in the C11-C15 region, showed that inactive analogues protrude into regions in space not occupied by active analogues. These structural studies indicate that multiple regions are important for 5-lipoxygenase inhibition by both 15-HETE and 15-HEDE analogues and that no single region plays a predominant role in inhibition.
Asunto(s)
Araquidonato Lipooxigenasas/antagonistas & inhibidores , Ácidos Hidroxieicosatetraenoicos/síntesis química , Inhibidores de la Lipooxigenasa , Animales , Basófilos/enzimología , Ácidos Hidroxieicosatetraenoicos/farmacología , Indicadores y Reactivos , Leucemia Experimental/enzimología , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Ratas , Espectrofotometría Infrarroja , Relación Estructura-ActividadRESUMEN
2-[(Phenylthio)methyl]pyridine derivatives inhibited the dermal reverse passive Arthus reaction (RPAR) in the rat. In the same model, indomethacin was inactive, and hydrocortisone was active. Compounds Ia-d also significantly reduced exudate volume and white blood cell accumulation in the pleural RPAR. This pattern of activity was similar to that of hydrocortisone and different from that of indomethacin.
Asunto(s)
Antiinflamatorios/síntesis química , Piridinas/síntesis química , Animales , Bioensayo , Carragenina , Hidrocortisona/farmacología , Indometacina/farmacología , Leucocitos/efectos de los fármacos , Masculino , Pleura/efectos de los fármacos , Piridinas/farmacología , Ratas , Ratas Endogámicas , Piel/efectos de los fármacosRESUMEN
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.