Novel fluorinated antiinflammatory steroid with reduced side effects: Methyl 9α-fluoroprednisolone-16-carboxylate

Article abstract of DOI:10.1002/jps.2600830406

In an effort to test the hypothesis that 9α-fluorination of a steroidal antedrug would enhance receptor binding affinity and local antiinflammatory activity, without concomitantly increasing adverse systemic effects, a fluorinated analog, 10, of methyl 11β,21-dihydroxy-3,20-dioxo-1,4- pregnadiene-16α-carboxylate (DP16CM, 1) was synthesized and evaluated. In the acute rat croton oil-induced ear edema bioassay. 10 was found to be twice as potent as 1. This increase in topical potency was consistent with enhanced binding affinity of 10, relative to 1. The IC₅₀ values for displacement of [³H] dexamethasone from glucocorticoid receptors of rat hepatoma tissue culture cells were 0.16, 1.2, and 0.03 μM for 10, 1, and prednisolone, respectively. Following multiple topical ID₅₀ applications of prednisolone, 1, and its new fluorinated analog, 10, in the rat subacute croton oil- induced ear edema bioassay, only prednisolone exhibited significant untoward effects, such as reduction in relative thymus and adrenal weights, plasma corticosterone levels, and normal body weight gain. Thus, while fluorination of 1 enhanced its topical potency, there was not a concomitant increase in untoward systemic effects. This lack of adverse systemic effects is ostensibly due to the presence of the metabolically labile 16-carboxylate ester moiety.