In continuing efforts to synthesize potent, anti-inflammatory
steroids devoid of systemic side effects, methyl 9 alpha-fluoro-11 beta,17 alpha,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate (
FP16CM) and its 21-acetate derivative (
FP16CMAc) were recently synthesized and screened in animal models of
inflammation. The compounds have now been assessed for high-affinity
glucocorticoid receptor binding and
glucocorticoid-mediated inhibition of
nitric oxide (NO) generation in an in vitro RAW 264.7 macrophage cell culture system. Relative potencies for
glucocorticoid receptor binding were 1, 1.7, and 2.4 for
prednisone (P) (IC50 = 287 nM),
FP16CM, and
FP16CMAc, respectively. Concomitant relative potencies for inhibition of NO generation by macrophages stimulated with
lipopolysaccharide were 1, 0.92 and 1.9 for P (IC50 = 126 nM),
FP16CM, and
FP16CMAc, respectively. Collectively, results suggest that the novel antedrugs are active
anti-inflammatory agents. The 9 alpha-fluoro and 21-acetate substituent may contribute to enhanced topical potency, increased receptor binding affinity and inhibitory effects on NO generation. Inhibition of vasoactive NO may be one anti-inflammatory action of the steroidal antedrugs in vivo. Collectively, results suggest that these agents may be useful for topical application in allergic/inflammatory diseases.