Rj. Little et al., Soft drugs based on hydrocortisone: The inactive metabolite approach and its application to steroidal antiinflammatory agents, PHARM RES, 16(6), 1999, pp. 961-967
Purpose. The soft drug approach was applied to the design of analogs of hig
hly potent synthetic steroids but with a metabolically labile ester group w
hich 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 poten
t steroid and had a highly significant separation of topical from systemic
activity. However, the compound demonstrated greater than expected stabilit
y 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 ac
tivity as measured in the tests presented here. The anticipated hydrolytic
instability of the compounds was not corroborated, however, in view of othe
r results, the interpretation is allowed that the rapid hydrolysis of the u
nbound fraction of the drug is an important factor in its lack of systemic
effects.