Fourteenth Annual Grant Winners 2013-2014
Development of Novel Potent Yet Safer Anti-inflammatory Steroids
Lisa Deziel-Evans, Pharm.D.,Ph.D.,BCPS,FASHP (HPD-PHR)
Faculty and Students
Hugh M. McLean, Pharm.D., Ph.D. (HPD-PHR)
Michelle Clark, Ph.D. (HPD-PHR)
Dhanush Haspula, B.S. (HPD-PHR)
Chronic inflammatory diseases affect approximately 10% of the U.S. population. Although both anti-inflammatory steroids (glucocorticoids) and non-steroidal anti-inflammatory drugs (NSAIDS) are routinely used to provide palliative therapy for many of these maladies, there is still a distinct paucity of “safe” and effective drugs, particularly for long term therapy of many inflammatory diseases such as asthma, psoriasis, ulcerative colitis and rheumatoid arthritis.Glucocorticoids are usually considered to be the drugs par excellence for relieving inflammatory symptoms, however their therapeutic use is restricted due to their propensity to elicit potentially serious adverse effects, particularly their suppressive effects on pituitary function and the immune system. The main thrust of the proposed study is the development of anti-inflammatory steroids with diminished penchant to elicit untoward systemic effects, via the mutual prodrug approach. To this end, the primary strategy is to incorporate a metabolically labile moiety, a carboxylic acid ester, into the steroid molecule (prednisolone), which would undergo facile systemic biotransformation to the less active and more readily excretable steroidal carboxylic acid. Such steroid acid esters have been dubbed antedrugs. To further enhance the topical potency and local/systemic activity ratios of these antedrugs, they will be conjugated via an ester linkage to selected NSAIDS (such as ibuprofen and indomethacin) atthe 21 - position of the glucocorticoids. Conjugates such as these have been dubbed mutual prodrugs, primarily because it is conceivable that upon administration, they would be biotransformed into the glucocortoid and the NSAID, both of which could conceivably exhibit synergistic anti-inflammatory activity. The results of these studies should establish axiomatically if the conjugation of glucocorticoids that are “antedrugs”, and NSAIDS, is a fundamentally sound synthetic ploy in the development of potent yet safer anti-inflammatory steroids.