Synthesis and pharmacological evaluation of new topical anti-inflammatory steroids.
The purpose of this research was to develop new topical steroid derivatives showing reduced systemic effects. Pregna-16 alpha,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)-9 alpha-fluoro-11 beta,21-dihydroxy-3,20-dioxo-16 alpha, 17-(methyl, methoxycarbonylmethyl)methylenedioxy-1,4-pregnadiene (I), showed more or less the same activity as shown by prednisolone in the granuloma inhibition test. However, compound I showed higher activity in the ear oedema inhibition test when applied topically (ID50 = 0.002 mg), as compared to prednisolone (ID50 = 0.006 mg) and triamcinolone (ID50 = 0.026 mg). When compound I was applied to mice, and thymus involution was measured for judging systemic effects, it was found that compound I 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.
Sin
K S
KS
College of Pharmacy, Kangweon National University, Chuncheon, South Korea.
Lee
H J
HJ
Kim
H P
HP
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D011919:Rats, Inbred Strains; D013950:Thymus Gland / Q000187:drug effects; D014221:Triamcinolone / Q000031:analogs & derivatives
D000893:Anti-Inflammatory Agents; D014221:Triamcinolone