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

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 12; pp. 3209 - 3212
• Main Authors: Caturla, Francisco, Amat, Mercè, Reinoso, Raquel F., Córdoba, Mónica, Warrellow, Graham
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.06.2006; Elsevier
• Subjects: Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; COX-2; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - blood; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Humans; Isomerism; Lactones - blood; Lactones - chemical synthesis; Lactones - chemistry; Lactones - pharmacology; Male; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Prodrugs; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Pyridines - blood; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Rats; Rats, Wistar; Safrole - analogs & derivatives; Safrole - chemistry; Solubility; Sulfones - blood; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; Sulfoxides; Temperature; Thermodynamics; COX-2; Sulfoxides; Prodrugs; Prostaglandin-endoperoxide synthase; Rofecoxib; Etoricoxib; Rat; Cyclooxygenase 2; Diseases of the osteoarticular system; Furan derivatives; Arthritis; Cyclooxygenase 2 inhibitor; Selectivity; Racemic; Enantiomer; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Lactone; Prodrug; In vitro; Biological activity; Non steroidal antiinflammatory agent; In vivo; Vertebrata; Mammalia; Animal; Sulfoxide; Models; Oxidoreductases; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.03.052

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.