Soft drugs based on hydrocortisone: the inactive metabolite approach and its application to steroidal antiinflammatory agents.
OBJECTIVE
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.
Department of Chemistry, Universidad de los Andes, Mérida, Venezuela. rlittle@ciens.ula.ve
R J
RJ
Little
N
N
Bodor
T
T
Loftsson
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003470:Culture Media / Q000378:metabolism; D006099:Granuloma / Q000188:drug therapy; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006868:Hydrolysis; D007274:Injections, Intraperitoneal; D008297:Male; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley
D000893:Anti-Inflammatory Agents; D003470:Culture Media; D006854:Hydrocortisone