New potent topical anti-inflammatory steroids with reduced side effects: derivatives of steroid-16-carboxy esters.
Therapeutic use of anti-inflammatory steroids is limited due to their potential suppressive effects on pituitary-adrenal function and the immune system. Based on the antedrug concept, a new class of potent locally active compounds with reduced risk of side effects has been synthesized from prednisolone by introducing a metabolically labile methoxycarbonyl substituent at C-16. Results of topical application of the lead compound, methyl 11 beta,17 alpha,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-carboxylate (P16CM;1), showed that it was 14 times more potent than prednisolone and that it had a greatly reduced tendency to cause systemic side effects. In the present investigations, we have demonstrated that chemical modifications such as 17- and/or 21-esterifications and 17,21-acetonidation of 1 further enhance topical activity in the croton oil ear edema model in rats. Following multiple topical ID50 applications of 1 or its derivatives, no thymolysis was noted. In the carrageenan-soaked sponge model of acute inflammation, all derivatives were potent inhibitors of leukocyte migration, generation of PGE2, and release of elastase. Taken together, these results indicate that esterification or acetonidation of hydroxyl groups at the 17 and/or 21 position, in combination with a labile C-16 methoxycarbonyl group, increases topical activity without concomitantly increasing the risk of side effects.
Center for Anti-inflammatory Research, Florida A & M University, College of Pharmacy, Tallahassee 32307.
A S
AS
Heiman
I B
IB
Taraporewala
H M
HM
McLean
D
D
Hong
H J
HJ
Lee
D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D002351:Carrageenan; D002464:Cell Migration Inhibition; D003436:Croton Oil; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004591:Electrophoresis, Polyacrylamide Gel; D003368:Gossypium; D006099:Granuloma / Q000188:drug therapy; D007249:Inflammation / Q000201:enzymology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010196:Pancreatic Elastase / Q000378:metabolism; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013950:Thymus Gland / Q000187:drug effects
D000893:Anti-Inflammatory Agents; C059496:methyl 11,17,21-trihydroxy-3,20-dioxopregna-1,4-diene-16-carboxylate; D003436:Croton Oil; D002351:Carrageenan; D011239:Prednisolone; D010196:Pancreatic Elastase