RESUMO
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.
Assuntos
Ácidos Graxos Insaturados/síntese química , Ácidos Graxos Insaturados/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Tromboxanos/antagonistas & inibidores , Tromboxano-A Sintase/antagonistas & inibidores , Plaquetas/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes , Colágeno/farmacologia , Desenho de Fármacos , Humanos , Hidrazinas/metabolismo , Conformação Molecular , Estrutura Molecular , Inibidores de Fosfodiesterase/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Receptores de Tromboxanos/metabolismo , Relação Estrutura-Atividade , Tromboxano A2/química , Tromboxano-A Sintase/sangue , TrítioRESUMO
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.
