RESUMEN
A series of omega-disubstituted alkenoic acid derivatives were designed and synthesized as antithrombotic inhibitors of thromboxane A2 synthetase and thromboxane A2 receptor antagonists. Hexenoic acid derivatives with a 3-pyridyl group and a 4-(2-benzenesulfonamidoethyl)phenyl substituent were found to be optimal with regard to the dual mode of action. The most potent compound, (E)-6-(4-(2-(((4-chlorophenyl)sulfonyl)amino)ethyl)phenyl)-6-(3-pyridyl) hex-5-enoic acid (36), inhibits thromboxane A2 synthetase in gel-filtered human platelets with an IC50 value of 4.5 +/- 0.5 nM (n = 4), whereas an inhibitory effect on cyclooxygenase is seen only at a much higher concentration (IC50: 240 microM). Radioligand-binding studies with [3H]SQ 29,548 in washed human platelets revealed that 36 blocks the prostaglandin H2/thromboxane A2 receptor with an IC50 of 19 +/- 5 nM (n = 5) and is therefore 85-fold more potent than another combined thromboxane A2 synthetase inhibitor/receptor antagonist, Ridogrel (4). Compound 36 inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an EC50 of 1 microM (Ridogrel: 16 microM) and 100 nM, respectively, and was selected for further development.
Asunto(s)
Ácidos Grasos Insaturados/síntesis química , Ácidos Grasos Insaturados/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Receptores de Tromboxanos/antagonistas & inhibidores , Tromboxano-A Sintasa/antagonistas & inhibidores , Plaquetas/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes , Colágeno/farmacología , Diseño de Fármacos , Humanos , Hidrazinas/metabolismo , Conformación Molecular , Estructura Molecular , Inhibidores de Fosfodiesterasa/farmacología , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , Receptores de Tromboxanos/metabolismo , Relación Estructura-Actividad , Tromboxano A2/química , Tromboxano-A Sintasa/sangre , TritioRESUMEN
Glutathione (GSH) adducts and consecutive degradation products thereof are indications of reactive intermediates during drug metabolism. As demonstrated with the analgesic SX-PP 16 (4-amino-3,5-dibromacetanilide), however, interactions of a drug with GSH can be detected by labelling the GSH-stores with labelled cysteine, and consecutive administration of the unlabelled drug even at therapeutic doses. The GSH-adducts are sensitively and specifically traced by HPLC, applying column-switching and a combination of diode-array- and radioactivity detection. This approach seems to be much more sensitive than a classical GSH-depletion study. The structure of the main metabolite of SX-PP 16 (46% of urinary excretion) was elucidated as 3-bromo-4-amino-5-mercapturyl-acetanilid.
