Synthesis and pharmacological evaluation of new topical anti-inflammatory steroids

초록

The purpose of this research was to develop new topical steroid derivatives showing reduced systemic effects. Pregna-16α, 17-carboxycyclic acetal derivatives have been recently synthesized by reacting triamcinolone with methyl acetylalkanoate in the presence of a catalytic amount of perchloric acid. In testing for the anti-inflammatory activity of the compounds, rat cotton-pellet granuloma inhibition bioassay and mouse croton-oil-induced ear oedema inhibition bioassay were employed. One of the synthesized compounds, (22R)-9α-fluoro-11β, 21-dihydroxy-3, 20-dioxo-16α, 17-(methyl, methoxycarbonylmethyl) methylenedioxy-1, 4-pregnadiene (1), showed more or less the same activity as shown by prednisolone in the granuloma inhibition test. However, compound 1 showed higher activity in the ear oedema inhibition test when applied topically (ID<inf>50</inf>=0.002mg), as compared to prednisolone (ID<inf>50</inf>= 0.006mg) and triamcinolone (ID<inf>50</inf>=0.026mg). When compound 1 was applied to mice, and thymus involution was measured for judging systemic effects, it was found that compound 1 did not show any significant thymus involution up to 0.1 mg/mouse (systemic administration) and 0.5 mg/mouse (topical administration). Because of its significantly reduced systemic effects, this compound is a promising topical anti-inflammatory steroid.