Racemic and chiral sulfoxides as potential prodrugs of the COX-2 inhibitors Vioxx and Arcoxia.
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.
Caturla
Francisco
F
Department of Medicinal Chemistry, Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024 Barcelona, Spain. jfcaturl@almirall.es
Amat
Mercè
M
Reinoso
Raquel F
RF
Córdoba
Mónica
M
Warrellow
Graham
G
D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077613:Etoricoxib; D006801:Humans; D007536:Isomerism; D007783:Lactones / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012451:Safrole / Q000031:analogs & derivatives* / Q000737:chemistry; D012995:Solubility; D013450:Sulfones / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013696:Temperature; D013816:Thermodynamics
D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D011355:Prodrugs; D011725:Pyridines; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; D012451:Safrole; C005746:sulfoxide; D000077613:Etoricoxib