Session Speaker

Design, Synthesis and Evaluation of New Steroidal Anti-Inflammatory Antidrugs
Henry J Lee, Keller C. Thomas and Younes J. Errahali
USA

Anti-inflammatory glucocorticoids with moderate potency such as prednisolone have been widely used in the treatment of a variety of inflammatory disorders. The antedrug concept which was introduced in1982 represents a new approach for the synthesis of safer local anti-inflammatory without systemic adverse effects by inactivating the steroid upon entry into circulation from applied site. Differences in structural and pharmacokinetic properties of glucocorticoid preparations are important in using them for clinical treatment. A considerable research effort has been committed to the chemical modifications of glucocorticoids, with expectation of increasing their potencies and minimizing systemic adverse effects.

Many anti-inflammatory glucocorticoid ante drugs such as 21-carboxylic esters and amides derivatives, ring-fused isoxazoline and oxime derivatives, ring-fused ketal derivatives, spiro enone derivatives, steroid-NSAID conjugates, 21-thioalkylether derivatives and 17,21-acetonide derivatives had been synthesized.

The pharmacology evaluations were performed that included cotton pellet granuloma bioassay, relative thymus weight, plasma corticosterone level, ear-edema bioassay, and rat liver cytosol GC receptor binding study. Many of these antedrug glucocorticoid derivatives exhibited desired anti-inflammatory potency, included high binding affinities to the receptors, significant inhibitory effects on the nitric oxide (NO) and other proinflammatory molecules. The metabolism study of this antedrugs in rat plasma showed rapid hydrolysis to inactive metabolites. Support by NIH-grants S06 GM08111