Racemic and chiral sulfoxides as potential prodrugs of 4-pyrone COX-2 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 13; pp. 3605 - 3608
• Main Authors: Caturla, Francisco, Amat, Mercè, Reinoso, Raquel F., Calaf, Elena, Warrellow, Graham
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.07.2006; Elsevier
• Subjects: Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; COX-2; Crystallography, X-Ray; Cyclooxygenase 1 - drug effects; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Drug Evaluation, Preclinical; Humans; Male; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology. Drug treatments; Prodrugs; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; Sulfoxides; Sulfoxides - chemical synthesis; Sulfoxides - chemistry; Sulfoxides - pharmacology; COX-2; Sulfoxides; Prodrugs; Rat; Sulfone; Cyclooxygenase 2; Cyclooxygenase 2 inhibitor; Selectivity; Racemic; Structure activity relation; Enantiomer; Chemical synthesis; Enzyme; Rodentia; Pyran derivatives; Oral administration; Enzyme inhibitor; Prodrug; Pyranone derivatives; In vitro; Non steroidal antiinflammatory agent; In vivo; Vertebrata; Mammalia; Animal; Sulfoxide; Oxidoreductases; Fluorine Organic compounds
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.03.101

The enantiomeric synthesis and profiling of sulfoxide-based prodrugs of potent COX-2 inhibitors discovered at Almirall are reported. The preparation of the sulfoxide analogues 7, 8, and 9 and their enantiomerically pure forms is discussed as well as their ability to act as prodrugs of the potent and selective sulfone-containing COX-2 inhibitors 1, 2, and 3. Sulfoxide derivatives 7 and 9 were shown to be rapidly transformed in vivo into the corresponding sulfone derivatives 1 and 3, after oral administration to rats.