RESUMEN
The synthesis and pharmacological evaluation of new water-soluble phosphoramidate derivatives of the COX-2 selective inhibitor cimicoxib (4) are described. The sulfonylphosphoramidic acid derivative 10 was converted to 4 in human plasma and showed excellent in vivo activity in the rat carrageenan-edema test. Pharmacokinetic evaluation in dogs indicated that 10 behaved as a prodrug, immediately converting to 4 and giving an identical profile to that of the parent compound. These results represent the first description of phosphoramidic acids as prodrugs for the sulfonamido group. Compound 10 also exhibited an important and sustained analgesic effect in the hyperalgesia test in rats and a high aqueous solubility at pH higher than 7. This profile led to the selection of 10 (UR-14048) for further development in the parenteral treatment of acute pain.
Asunto(s)
Amidas/química , Inhibidores de la Ciclooxigenasa/síntesis química , Imidazoles/síntesis química , Ácidos Fosfóricos/química , Ácidos Fosfóricos/síntesis química , Profármacos/síntesis química , Sulfonamidas/síntesis química , Enfermedad Aguda , Animales , Carragenina , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacología , Perros , Edema/tratamiento farmacológico , Semivida , Humanos , Hiperalgesia/tratamiento farmacológico , Imidazoles/farmacocinética , Imidazoles/farmacología , Isoenzimas/antagonistas & inhibidores , Masculino , Proteínas de la Membrana , Dimensión del Dolor , Ácidos Fosfóricos/farmacocinética , Ácidos Fosfóricos/farmacología , Profármacos/farmacocinética , Profármacos/farmacología , Prostaglandina-Endoperóxido Sintasas , Ratas , Ratas Wistar , Solubilidad , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , AguaRESUMEN
The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.