RESUMEN
The synthesis and in vitro evaluation of the acetamidine derivatives of hetero-substituted lysine and homolysine analogues have identified potent inhibitors of human nitric oxide synthase enzymes, including examples with marked selectivity for the inducible isoform.
Asunto(s)
Acetamidas/síntesis química , Inhibidores Enzimáticos/síntesis química , Lisina/análogos & derivados , Lisina/síntesis química , Óxido Nítrico Sintasa/antagonistas & inhibidores , Acetamidas/farmacología , Inhibidores Enzimáticos/farmacología , Humanos , Indicadores y Reactivos , Isoenzimas/antagonistas & inhibidores , Lisina/farmacología , Óxido Nítrico Sintasa de Tipo II , Ornitina/análogos & derivados , Ornitina/farmacología , Sulfuros/farmacología , Sulfonas/farmacologíaRESUMEN
The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl] benzene (38) (pKb 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.
Asunto(s)
Factor de Activación Plaquetaria/antagonistas & inhibidores , Compuestos de Amonio Cuaternario/síntesis química , Animales , Sitios de Unión , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Células Cultivadas , Masculino , Inhibidores de Agregación Plaquetaria/farmacología , Compuestos de Amonio Cuaternario/metabolismo , Compuestos de Amonio Cuaternario/farmacología , Conejos , Relación Estructura-ActividadAsunto(s)
Inhibidores Enzimáticos , Quinurenina/biosíntesis , Compuestos Orgánicos , Triptófano Oxigenasa/antagonistas & inhibidores , Triptófano/metabolismo , Animales , Ansiedad/fisiopatología , Encéfalo/metabolismo , Ácido Hidroxiindolacético/metabolismo , Hígado/metabolismo , Ratas , Serotonina/biosíntesis , Triptófano/farmacocinética , Triptófano Oxigenasa/farmacologíaRESUMEN
The interaction of novel diacylglycerol analogues at the recognition site on protein kinase C has been evaluated using a modified [3H]phorbol dibutyrate binding assay and an established kinase activation assay. Studies with the 3-methyl analogues of 1,2-dihexanoyl-sn-glycerol have revealed a preferred stereochemical configuration at the C-3 position. Other chemical modifications have extended existing structure/activity relationships by showing that carbamates and sulphonyl esters cannot substitute for carboxylate esters and that cyclic acyl groups are active. Thus, most, if not all of the functionalities in the diacylglycerol molecule are required for interaction at the receptor on protein kinase C. Stereochemical specificity is required at C2 and C3.