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At least 19 recordsLinked to original sources
PubMed2000

New steroidal anti-inflammatory antedrugs: methyl 21-desoxy-21-chloro-11beta,17alpha-dihydroxy-3,20-dioxo-1, 4-pregnadiene-16alpha-carboxylate, methyl 21-desoxy-21-chloro-11beta-hydroxy-3,20-dioxo-1, 4-pregnadiene-16alpha-carboxylate, and their 9alpha-fluoro derivatives*.

To a series of 21-desoxy-21-chloro-corticosteroids, a metabolically labile methoxycarbonyl group at C-16 has been incorporated. The approach is to synthesize locally active compounds that are hydrolyzed to inactive and readily excretable acid metabolites upon entry into the systemic circulation. Novel antedrugs were evaluated for anti-inflammatory activity and their adverse effects in an acute and semichronic croton oil-induced ear edema bioassay. Binding affinity to glucocorticoid receptors and induction of L-tyrosine-2-oxoglutarate aminotransferase were studied in hepatoma tissue culture cells. After a single topical application in the croton oil-induced ear edema bioassay, treatment with all the compounds resulted in dose-dependent inhibition of edema. From these dose-response profiles, the following ID(50) values (nmol/ear resulting in a 50% reduction of edema) were calculated: 540, 618, 454, and 346 nmol for prednisolone (P), methyl 21-desoxy-21-chloro-11beta,17alpha-dihydroxy-3,20-dioxo-1, 4-pregnadien-16alpha-carboxylate (PClCM), methyl 21-desoxy-21-chloro-11beta,17alpha-dihydroxy-9alpha-fl uoro-3, 20-dioxo-1,4-pregnadien-16alpha-carboxylate (FPClCM), and methyl 21-desoxy-21-chloro-9alpha-fluoro-11beta-hydroxy-3,20-dioxo- 1, 4-pregnadien-16alpha-carboxylate (FDPClCM), respectively. Results of the 5-day rat croton oil ear edema bioassay indicated that, in contrast with the parent compound P, the novel steroidal antedrugs did not significantly alter body weight gain, thymus weights, or plasma corticosterone levels. The binding affinities for cytosolic hepatoma tissue culture glucocorticoid receptors were 33, 201, 471, 5304, and 3765 nM for P, PClCM, FPClCM, methyl 21-desoxy-21-chloro-11beta-hydroxy-3,20-dioxo-1, 4-pregnadien-16alpha-carboxylate (DPClCM), and FDPClCM, respectively. Collectively, results of these investigations suggest that modifications of P, which included replacement of 21-hydroxyl group with chlorine and addition of 16-methoxycarbonyl group with or without 17-hydroxyl moiety, retained the topical anti-inflammatory activity of the parent compound P without significant adverse systemic effects.

Animals↗
PubMed2000

[Studies on the production of 16 beta-methyl-11 alpha,17 alpha,21-trihydroxy-1,4-pregnadiene-3,20-dione from 16 beta-methyl-17 alpha,21-dihydroxy-1,4-pregnadiene-3,20-dione-21-acetate by Absidia].

An Absidia sp. 28 strain was shown to have higher activity of 11 alpha-hydroxylation using 16 beta-methyl-17 alpha,21-dihydroxy-1,4-pregnadiene-3,20-dione as a substrate. It was found that 21-acetylization of substrate could increase 11 alpha-hydroxylation rate conspicuously. The yield of the 11 alpha-hydroxylation by this strain was 73% in the conversion of 0.5% concentration of 21-acetated substrate under optimum conditions.

Absidia↗
PubMed1997

New steroidal anti-inflammatory antedrugs: methyl 3,20-dioxo-9 alpha-fluoro-11 beta,17 alpha,21-trihydroxy-1,4-pregnadiene-16 alpha-carboxylate and methyl 21-acetyloxy-3,20-dioxo-11 beta, 17 alpha-dihydroxy-9 alpha-fluoro-1,4-pregnadiene-16 alpha-carboxylate.

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, 9 alpha-fluoro-methyl 11 beta, 17 alpha, 21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16 alpha-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 modification 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.

Administration, Topical↗
PubMed1987

Synthesis of new antiinflammatory steroidal 20-carboxamides: (20R)- and (20S)-21-(N-substituted amino)-11 beta,17,20-trihydroxy-3,21-dioxo-1,4- pregnadiene.

The synthesis and antiinflammatory activities of new steroidal 20-carboxamides, (20R)- and (20S)-21-(N-substituted amino)-11 beta,17,20-trihydroxy-3,21-dioxo-1,4-pregnadiene are described. These compounds were prepared from the respective isomer of 20-dihydroprednisolonic acid, (20R)- and (20S)-11 beta,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oic acid, by coupling with primary amines after the activation of the steroid acid with N,N1-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole. Confirmation of the configurational assignment at C-20 of the 20-carboxamides was achieved by reduction of methyl (20R)- and (20S)-11 beta,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate to the known stereochemistry at C-20 of (20R)- and (20S)-11 beta,17,20,21-tetrahydroxy-3-oxo-1,4-pregnadiene The topical antiinflammatory activities of these steroidal 20-carboxamides were assessed by the croton oil induced ear edema assay and their local and systemic antiinflammatory activities by the cotton pellet granuloma bioassay. Results of these investigations suggest a structure-activity relationship where carboxamide derivatives with the 20(R)-hydroxy configurations exhibit higher potency than those with the 20-(S)-hydroxy configurations. The amides of steroidal 21-oic acids with high local antiinflammatory potency exhibited systemic activities unlike the corresponding esters of steroidal 21-oic acids, which are devoid of systemic activities.

Animals↗
PubMed1983

Biosynthesis of 3 beta-hydroxy-5,7-pregnadien-20-one by the horse fetal gonad.

The production of equilin and the other ring B-unsaturated estrogens by the pregnant mare is anomalous in that they are biosynthesised by a cholesterol-independent pathway. Fetal horse gonads were incubated with tritiated sodium acetate and radiochemically pure 3 beta-hydroxy-5,7-pregnadien-20-one and 3 beta-hydroxy-5,7-androstadien-17-one were isolated. A fetal gonad--placental system is proposed for equilin production, 3 beta-hydroxy-5,7-pregnadien-20-one being a precursor for 3 beta-hydroxy-5,7-androstadien-17-one in the fetal gonad and the latter being the precursor of equilin in the placenta. The nature of the possible precursor of 3 beta-hydroxy-5,7-pregnadien-20-one is discussed.

Animals↗
PubMed1985

Synthesis of a new anti-inflammatory steroidal acid ester: methyl 11 beta-hydroxy-3,20-dioxo-1,4-pregnadien-21-oate.

The synthesis and anti-inflammatory activity of a new steroidal acid ester, methyl 11 beta-hydroxy-3,20-1,4-pregnadien-21-oate (5), are described. This compound has been prepared via three different synthetic routes. The first involves oxidation of the benzoate 3 to the aldehyde 4 followed by a Mattox-type rearrangement of the side chain in conjunction with elimination of the benzoyloxy group. The second method, prolonged reaction of 1-dehydrocorticosterone (8) with methanolic cupric acetate, affords methyl ester 5 in low yield. The third approach consists of selective oxidation at C-20 of the methyl 11 beta, 20 alpha and 20 beta-dihydroxy-3-oxo-1,4-pregnadien-21-oates (7a and 7b) with sulfur trioxide-pyridine complex. The local anti-inflammatory activities of the new ester 5 and intermediates 3, 4, 7a and 7b were determined by the cotton-pellet granuloma assay in rats. The anti-inflammatory activity of the title compound is equal to that of the parent steroid, prednisolone. However, unlike the latter compound, the ester does not cause reduction of adrenal and thymus weights or a lowering of plasma corticosterone levels.

Administration, Topical↗
PubMed1989

Studies on topical antiinflammatory agents. III. Synthesis of 17 alpha-acyloxy-9 alpha-fluoro-11 beta-hydroxy-16 beta-methyl-1,4-pregnadiene-3,20-dione 21-thio derivatives and related compounds.

A series of 21-thio derivatives of 9 alpha-fluoro-11 beta,17 alpha-dihydroxy-16 beta-methyl-1,4-pregnadiene-3, 20-dione 17-esters and related compounds were synthesized and evaluated as topical antiinflammatory agents. These compounds were prepared by the reaction of 9 alpha-fluoro-11 beta,17 alpha,21-trihydroxy-16 beta-methyl-1,4-pregnadiene-3, 20-dione (betamethasone, I) 17-ester derivatives and various mercapto compounds. A structure-activity relationship study revealed that the structural combination of a thio group at the 21-position and an ester group at the 17-position contributed to vasoconstrictive activity. Among these compounds, the 21-methylthio 17-propanoate compound (6) was found to have the most potent activity, being more potent than betamethasone 17-valerate (BV).

Administration, Topical↗
PubMed1983

Identification of 3 beta-hydroxy-5,7-pregnadien-20-one and 3 beta-hydroxy-5,7-androstadien-17-one as endogenous steroids in the fetal horse gonad.

The 5,7-dienes, 3 beta-hydroxy-5,7-pregnadien-20-one and 3 beta-hydroxy-5,7-androstadien-17-one were extracted from fetal horse gonads and purified by solvent partition, thin-layer chromatography and high performance liquid chromatography. The isolated steroids were identified by comparison with the synthetic steroids using ultraviolet and mass spectroscopy and by gas chromatography-mass spectroscopy. The identification of these compounds as endogenous steroids, together with the data on their biosynthesis reported previously, support the proposal that in the fetal horse gonad there is a 5,7-diene pathway biosynthesizing 3 beta-hydroxy-5,7-androstadien-17-one, which is the proposed precursor for equilin in the placenta.

Androstadienes↗
PubMed1976

[Studies on the Pharmacology of 6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolon valerate) (author's transl)].

The topical and systemic anti-inflammatory action of 6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) was studied in the rat in comparison with fluocortolone, diflucortolone and some other corticoids. In addition the effect of the compounds studied on the following parameters of corticoid activity was examined in the rat: body weight and weights of thymus, spleen and adrenals; blood sugar concentration and liver glycogen content; diuresis and Na+ and K+ elimination with the urine; the binding of diflucortolone and some diflucortolone-21-esters to the cytoplasmic corticoid receptor of the rat's thymus was also determined. In all tests diflucortolone was shown to be a corticoid with very potent topical and systemic action. Diflucortolone valerate showed the same potent anti-inflammatory action on topical application as the unesterified compound. After subcutaneous administration, however, the systemic corticoid action of the valerate was considerably inferior to that of diflucortolone on account of the kinetics of the more lipid soluble ester.

Adrenal Glands↗
PubMed1978

[Human-pharmacokinetic Studies on Penetration Kinetics of a 6 alpha-Fluoro-9 alpha-chloro-16 alpha-methyl-delta 1,4-pregnadiene-11 beta-dihydroxy-3,20-dione-21-trimethyl-acetic acid (Clocortolone Trimethyl-acetic acid) after e picutaneous application].

Investigation on 6 alpha-fluoro-9 alpha-chloro-16 alpha-methyl-delta 1,4-pregnadiene-11 beta-dihydroxy-3,20-dione-21-trimethylacetic acid (clocortolone trimethylacetic acid) are reported. The aim of the trial was to prove the penetration kinetics of the steriod into the skin. Three healthy female subjects took part in the investigations. They were treated with an oil-water emulsion of the substance on two spots on the back, after having observed alcohol abstinence. One of the treated spots was stripped after 30 min, the second after 60 min using the "Tesafilm" stripping method. The strips were then analysed gaschromatographically on the presence of clocortolone-trimethylacetic acid. It could be shown that the steroid penetrates into the skin up to the 12th-14th strips, building up a certain congestion of the substance at this time because of reaching the stratum corneum, as we suppose. At this place a depot is built of which probably only a very small or no permeation into the system occurs, as clocortolone could not be detected either in the subjects' serum nor in the urine.

Administration, Topical↗
PubMed1994

Direct radioimmunoassay of progesterone in bovine plasma using danazol (17-alpha-2,4-pregnadien-20-yno(2,3-d)isoxazol-17-ol) as a displacing agent.

The majority of progesterone in plasma is bound to cortisol-binding globulin and albumin carrier proteins. In the determination of plasma progesterone concentration by radioimmunoassay (RIA), it is necessary to remove these carrier proteins or displace the hormone from them. In the present study, we have examined the suitability of danazol (17-alpha-2,4-pregnadien-20-yno(2,3-d)isoxazol-17-ol), a synthetic steroid, to displace progesterone from plasma proteins in a direct RIA of bovine plasma. Accordingly, the progesterone content of bovine plasma samples was measured with a RIA using danazol as a displacing agent (direct RIA) and compared with results obtained with a RIA incorporating a preliminary solvent extraction step (extraction RIA). Danazol did not alter the standard curve for progesterone. Sensitivity (ED80) of the direct RIA (9.8 pg/tube) was comparable to that of the extraction RIA (10.3 pg/tube). Results for progesterone assayed in the direct RIA correlated well (r = 0.99) with the results obtained with the extraction RIA. The direct RIA was shown to be accurate; the mean recovery of known amounts of progesterone added to a sample of pooled bovine plasma was 98.5% +/- 3.29 (SEM). The direct RIA intra-assay coefficient of variation (CV) RIA for samples within the low concentration range (0.1-1.0 ng/mL), the medium concentration range (1.0-3.0 ng/mL) and the high concentration range (3.0-6.0 ng/mL) of progesterone were 8.1%, 8.3% and 7.73%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗