Focused efforts have been made to increase local-to-systemic activity ratios of potent anti-inflammatory
steroids for local and/or topical applications. The approach taken in the present investigation is based upon the concept of "antedrug," defined as a locally active compound that exerts its action at the application site but rapidly undergoes a predictable biotransformation to an inactive metabolite that is readily excreted upon entry into the systemic circulation. In continuing efforts to synthesize potent, anti-inflammatory
steroids without systemic
glucocorticoid activities, 9 alpha-fluoro-methyl 11 beta, 17 alpha, 21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate (
FP16CM) and its 21-acetate derivative (
FP16CMAc) have been synthesized and screened. Novel antedrugs were evaluated for antiinflammatory activity in the acute
croton oil-induced ear
edema bioassay, adverse systemic effects in the 5-day
croton oil model, receptor binding, and concomitant L-tyrosine-2-oxoglutarate
aminotransferase (EC 2.6.1.5) (TAT) enzyme induction in HTC cells in culture. Following a single topical application in the
croton oil-induced ear
edema bioassay, treatment with all compounds resulted in dose-dependent inhibition of
edema. From these dose-response profiles, the following ID50 values (nmol resulting in a 50% reduction of
edema) were calculated: 817, 540, 266, and 67 for
hydrocortisone (HC),
prednisolone (P),
FP16CM, and
FP16CMAc, respectively. Calculated relative potencies, setting HC = 1.0, were P, 1.5;
FP16CM, 3.1, and
FP16CMAc, 12.2. Results of the 5-day rat
croton oil ear
edema bioassay indicated that, in contrast to the parent compound P, the novel steroidal antedrugs did not significantly alter
body weight gain, thymus weights, or plasma
corticosterone levels. Relative binding potencies for cytosolic HTC
glucocorticoid receptors were 1.0, 20.1, 5.4, and 2.5 for HC, P,
FP16CM, and
FP16CMAc, respectively. As predicted by the antedrug concept,
FP16CM and
FP16CMAc were very weak agonists for induction of TAT in HTC cells. Collectively, results of these investigations suggest that modification of P, which included addition of the 9-fluoro and 16-methoxycarbonyl group alone or in conjunction with a 21-acetoxy moiety, increase topical anti-inflammatory activity without significant adverse systemic effects. These new antedrugs may be useful as anti-inflammatory
steroids for local applications.