Racemic and chiral sulfoxides as potential prodrugs of the COX-2 inhibitors Vioxx ® and Arcoxia

The enantiomeric synthesis and profiling of sulfoxide-based rofecoxib and etoricoxib (Merck) prodrugs are reported. The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were seen when compared with rofecoxib.