- New steroidal anti-inflammatory antedrugs: Methyl 3,20-dioxo-9α- fluoro-11β,17α,21-trihydroxy-1,4-pregnadiene-16α-carboxylate and methyl 21-acetyloxy-3,20-dioxo-11β,17α-dihydroxy-9α-fluoro-1,4-pregnadiene-16α- carboxylate
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Focused efforts have been made to increase local-to-systemic activity ratios of potent anti-inflammatory steroids for local and/or topical applications. The approach taken in the present investigation is based upon the concept of 'antedrug,' defined as a locally active compound that exerts its action at the application site but rapidly undergoes a predictable biotransformation to an inactive metabolite that is readily excreted upon entry into the systemic circulation. In continuing efforts to synthesize potent, anti-inflammatory steroids without systemic glucocorticoid activities, 9α-flouro-methyl11β,17α,21-trihydroxy-3,20-dioxo-pregna-1,4- diene-16α-carboxylate (FP16CM) and its 21-acetate derivative (FP16CMAc) have been synthesized and screened. Novel antedrugs were evaluated for antiinflammatory activity in the acute croton oil-induced ear edema bioassay, adverse systemic effects in the 5-day croton oil model, receptor binding, and concomitant L-tyrosine-2-oxoglutarate aminotransferase (EC 2.6.1.5) (TAT) enzyme induction in HTC cells in culture. Following a single topical application in the croton oil-induced ear edema bioassay, treatment with all compounds resulted in dose-dependent inhibition of edema. From these dose- response profiles, the following ID50 values (nmol resulting in a 50% reduction of edema) were calculated: 817, 540, 266, and 67 for hydrocortisone (HC), prednisolone (P), FP16CM, and FP16CMAc, respectively. Calculated relative potencies, setting HC = 1.0, were P, 1.5; FP16CM, 3.1, and FP16CMAc, 12.2. Results of the 5-day rat croton oil ear edema bioassay indicated that, in contrast to the parent compound P, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights, or plasma corticosterone levels. Relative binding potencies for cytosolic HTC glucocorticoid receptors were 1.0, 20.1, 5.4, and 2.5 for HC, P, FP16CM, and FP16CMAc, respectively. As predicted by the antedrug concept, FP16CM and FP16CMAc were very weak agonists for induction of TAT in HTC cells. Collectively, results of these investigations suggest that modifications of P, which included addition of the 9-fluoro and 16-methoxycarbonyl group alone or in conjunction with a 21-acetoxy moiety, increase topical anti- inflammatory activity without significant adverse systemic effects. These new antedrugs may be useful as anti-inflammatory steroids for local applications.
- Heiman, Ann S.,Ko, Dong-Hoon,Chen, Meiqin,Lee, Henry J.
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p. 491 - 499
(2007/10/03)
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- Application of Curvularia sp to the hydrolysis of steroid pivalates
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As glucocorticoids have alkali - sensitive hydroxyacetylic side chain, conventional methods of removing of 21 - pivalates groups are risky. In this paper we described the hydrolysis of pivalates of some glucocorticoids by fungi imperfecti: Curvularia lunata, Curvularia tuberculata, Cylindrocladium simplex Meyer and Cunninghamella elegans. The highest yield of hydrolysis was found in the case of hydrocortisone and prednisolone pivalates with Curvularia lunata and Curvularia tuberculata. The other two tested enzymes gave in all studied cases null or extremely poor results.
- Kruszewska,Chmielowiec,Uszycka-Horawa
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p. 809 - 810
(2007/10/03)
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- Novel fluorinated antiinflammatory steroid with reduced side effects: Methyl 9α-fluoroprednisolone-16-carboxylate
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In an effort to test the hypothesis that 9α-fluorination of a steroidal antedrug would enhance receptor binding affinity and local antiinflammatory activity, without concomitantly increasing adverse systemic effects, a fluorinated analog, 10, of methyl 11β,21-dihydroxy-3,20-dioxo-1,4- pregnadiene-16α-carboxylate (DP16CM, 1) was synthesized and evaluated. In the acute rat croton oil-induced ear edema bioassay. 10 was found to be twice as potent as 1. This increase in topical potency was consistent with enhanced binding affinity of 10, relative to 1. The IC50 values for displacement of [3H] dexamethasone from glucocorticoid receptors of rat hepatoma tissue culture cells were 0.16, 1.2, and 0.03 μM for 10, 1, and prednisolone, respectively. Following multiple topical ID50 applications of prednisolone, 1, and its new fluorinated analog, 10, in the rat subacute croton oil- induced ear edema bioassay, only prednisolone exhibited significant untoward effects, such as reduction in relative thymus and adrenal weights, plasma corticosterone levels, and normal body weight gain. Thus, while fluorination of 1 enhanced its topical potency, there was not a concomitant increase in untoward systemic effects. This lack of adverse systemic effects is ostensibly due to the presence of the metabolically labile 16-carboxylate ester moiety.
- McLean,Khalil,Heiman,Lee
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p. 476 - 480
(2007/10/02)
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