RESUMEN

We have synthesized a fluorinated analogue of indomethacin bearing a 3,3,3-trifluoroprop-1-enyl group at its 2-position and evaluated its inhibitory activity towards the COX-1 and COX-2 enzymes in vitro. The results revealed that this fluorinated analogue exhibited much greater inhibitory activity and selectivity towards COX-2 than indomethacin. The increased affinity between the fluorinated analogue and COX-2 was attributed to a significant increase in van der Waals contacts (i.e. van der Waals contributions in ΔG were -13.80 kcal/mol for COX-1 and -18.46 kcal/mol for COX-2), explaining an effect of the fluorine substituent in enzyme selectivity. This newly synthesized fluorinated analogue therefore represents a potent and selective COX-2 inhibitor.

Asunto(s)

Ciclooxigenasa 2/metabolismo , Indometacina/química , Sitios de Unión , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/metabolismo , Indometacina/metabolismo , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Electricidad Estática