Soft drugs based on hydrocortisone: the inactive metabolite approach and its application to steroidal antiinflammatory agents.

摘要

PURPOSE: The soft drug approach was applied to the design of analogs of highly potent synthetic steroids but with a metabolically labile ester group which at the same time served as an activating group. METHODS: Several structural modifications of soft antiinflammatory steroids were synthesized and tested in several assays of biological activity. The hydrolytic stability of the compounds was also determined. RESULTS: One of the compounds synthesized was determined to be a very potent steroid and had a highly significant separation of topical from systemic activity. However, the compound demonstrated greater than expected stability in the hydrolysis studies. CONCLUSIONS: The goal of the soft drug approach has been achieved with the development of a highly potent drug which displays little or no systemic activity as measured in the tests presented here. The anticipated hydrolytic instability of the compounds was not corroborated; however, in view of other results, the interpretation is allowed that the rapid hydrolysis of the unbound fraction of the drug is an important factor in its lack of systemic effects.