RESUMEN
Synthesis and evaluation of novel series of indoline-1- or 3,4-dihydroquinoline-1(2H)-substituted carbothiohydrazide or carbohydrazide based small molecule compounds as thrombopoietin (TPO) receptor agonists are reported. Members of these compounds have been identified as full agonists of human c-mpl in BaF3/TPOR cell line. Indoline-1-carbohydrazide 9b exhibited reasonable pharmacokinetic profile.
Asunto(s)
Hidrazinas/química , Indoles/química , Quinolinas/química , Receptores de Trombopoyetina/agonistas , Animales , Línea Celular , Humanos , Hidrazinas/síntesis química , Hidrazinas/farmacocinética , Indoles/síntesis química , Indoles/farmacocinética , Ratas , Receptores de Trombopoyetina/metabolismo , Relación Estructura-ActividadRESUMEN
AIM: Imrecoxib is a novel and moderately selective COX-2 inhibitor. The aim of the present in vitro investigation was to study the formation of the major metabolite 4'-carboxylic acid imrecoxib (M2) and identify the enzyme(s) involved in the reaction. METHODS: The formation of M2 was studied in rat liver cytosol in the absence or presence of liver microsome. The formed metabolite was identified and quantified by LC/MS(n). In addition, to characterize the cytochrome P450 (CYP) isozymes involved in M2 formation, the effects of typical CYP inhibitors (such as ketoconazle, quinine, alpha-naphthoflavone, methylpyrazole, and cimetidine) on the formation rate of M2 were investigated. RESULTS: The formation of M2 from 4-hydroxymethyl imrecoxib (M4) was completely dependent on rat liver microsomes and NADPH. Enzyme kinetic studies demonstrated that the formation rate of M2 conformed to monophasic Michaelis-Menten kinetics. Additional experiments showed that the formation of M2 was induced significantly by dexamethasone and lowered by ketoconazole strongly and concentration-dependently. By comparison, other CYP inhibitors, such as alpha-naphthoflavone, cimetidine, quinine, and methylpyrazole had no inhibitory effects on this metabolic pathway. CONCLUSION: These biotransformation studies of imrecoxib in rat liver at the subcellular level showed that the formation of M2 occurs in rat liver microsomes and is NADPH-dependent. The reaction was mainly catalyzed by CYP 3A in untreated rats and in dexamethasone-induced rats. Other CYP, such as CYP 1A, 2C, 2D, and 2E, seem unlikely to participate in this metabolic pathway.