NEW STEROIDAL ANTIINFLAMMATORY ANTEDRUGS - METHYL 21-TRIHYDROXY-1,4-PREGNADIENE-16-ALPHA-CARBOXYLATE AND METHYL -ALPHA-FLUORO-1,4-PREGNADIENE-16-ALPHA-CARBOXYLATE

Focused efforts have been made to increase local-to-systemic activity ratios of potent anti-inflammatory steroids for local and/or topical a pplications. 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 read ily excreted upon entry into the systemic circulation. In continuing e fforts to synthesize potent, anti-inflammatory steroids without system ic glucocorticoid activities, 9 alpha-fluoro-methyl11 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 scr eened. Novel antedrugs were evaluated for antiinflammatory activity in the acute croton oil-induced ear edema bioassay, adverse systemic eff ects in the 5-day croton oil model, receptor binding, and concomitant L-tyrosine-2-oxoglutarate aminotransferase (EC 2.6.1.5) (TAT) enzyme i nduction in HTC cells in culture. Following a single topical applicati on in the croton oil-induced ear edema bioassay, treatment with all co mpounds resulted in dose-dependent inhibition of edema. From these dos e-response profiles, the following ID50 values (nmol resulting in a 50 % reduction of edema) were calculated: 817, 540, 266, and 67 for hydro cortisone (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 nov el steroidal antedrugs did not significantly alter body weight gain, t hymus weights, or plasma corticosterone levels. Relative binding poten cies for cytosolic HTC glucocorticoid receptors were 1.0, 20.1, 5.4, a nd 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 investig ations suggest that modifications 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 usef ul as anti-inflammatory steroids for local applications. (C) 1997 by E lsevier Science Inc.