In vitro anti-inflammatory activities of new steroidal antedrugs: [16α,17α-d] Isoxazoline and [16α,17α-d]-3′-hydroxy-iminoformyl isoxazoline derivatives of prednisolone and 9α-fluoroprednisolone

A series of new anti-inflammatory steroidal antedrugs with C-16,17-isoxazoline ring system were synthesized and their pharmacological activities were evaluated. We reported earlier that these compounds are promising antedrugs based on the results of 5-day rat croton oil ear edema assay. In the present study, most of these compounds showed high binding affinities to the glucocorticoid receptor of liver cytosol. 21-Acetyloxy-9α-fluoro-11β-hydroxy-3,20-dioxo-1,4-pregnadieno [16α,17α-d] isoxazoline (FP-ISO-21AC) and 11β,21-dihydroxy-9α-fluoro-3,20-dioxo-1,4-pregnadieno [16α,17α-d] isoxazoline (FP-ISO-21OH) were found 5.0-, 5.3-fold more potent than prednisolone, respectively. Inhibitory effects of the antedrugs on the nitric oxide (NO) production were assessed using LPS-stimulated RAW 264.7 murine macrophage cells. All these steroidal antedrugs exhibited concentration-dependent inhibition of NO production, but their relative potencies were lower than prednisolone. In vitro metabolism study in rat plasma showed that FP-ISO-21AC and 21-acetyloxy-9α-fluoro-11β-hydroxy-3,20-dioxo-1,4-pregnadieno [16α,17α-d]-3′-hydroxyiminoformyl isoxazoline (FP-OXIM-21AC) were hydrolyzed rapidly, with the half-lives of 2.1 and 4.2 min, respectively. The half-lives of FP-ISO-21OH and 11β,21-dihydroxy-9α-fluoro-3,20-dioxo-1,4-pregnadieno [16α,17α-d]-3′-hydroxyiminoformyl isoxazoline (FP-OXIM-21OH) were 92.2 and 110.2 min, respectively.