3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17alpha-ethynyl-estradiol-induced cholestasis in rats.

3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), the 7alpha-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17alpha-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6-6.0 micromol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO(3)(-)), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO(3)(-) output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na(+) taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease.

Synthesis of 21,21-difluoro-3 beta-hydroxy-20-methylpregna-5,20-diene and 5,16,20-triene as potential inhibitors of steroid C17(20) lyase.

Novel 21,21-difluorovinyl steroids, designed as difluorinated C20(21) enol mimics of pregnenolone, were targeted as potential mechanism-based inhibitors of C17(20) lyase, a crucial enzyme in the biosynthesis of testosterone. Addition of (difluoromethyl)diphenylphosphine oxide reagent to 17-acetyl steroids was the approach chosen for the construction of these compounds. Of particular interest were the abnormal Wittig products which formed during attempted preparation of the triene 9. The target difluoroolefin 3 was found to be a moderately potent, time-dependent inhibitor of the enzyme.

Novel steroidal vinyl fluorides as inhibitors of steroid C17(20) lyase.

20-fluoro-17(20)-pregnenolone derivatives were designed as enol mimics of pregnenolone. All of the targeted, novel fluoroolefins were potent inhibitors of C17(20) lyase.

Side chain modified sterols as probes into insect molting hormone metabolism. II: synthesis of monofluorocholesterols.

The hydroxylations of the cholesterol side chain at C-20, 22, and 25 are key terminal events in ecdysone biogenesis. We have prepared the C-20, C-22, C-24, and C-25 monofluorinated cholesterols as potential inhibitors of these hydroxylation events, and preliminary bioassay results in Manduca sexta are reported. The synthesis of [26(14)C]-20-fluorocholesterol is also described. Although the 20-, 22-, and 25-monofluorocholesterols do not appear to affect larval growth and development, the 24-fluoro isomer shows a moderate retardation of growth and a modest increase in mortality.

Synthesis and topical antiinflammatory properties of 17,21-bis(acetyloxy)-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione and related 2-halogenated compounds.

Introduction of a halogen atom at C-2 of steroid 3-ketofluorohydrins, obtained from the corresponding 5alpha,6alpha-epoxides by trans-diaxial opening with hydrofluoric acid, prevents the 6beta-fluorine atom from undergoing rearrangement to the more stable 6alpha configuration when the 5-tert-hydroxyl is split off to yield to yield a conjugated double bond. Two processes were investigated for the synthesis of 17,21-bis(acetyloxy)-6beta-fluoro-1,4,9(11)-triene-3,20-dione (24a) and the related 2-bromo compound 24b starting from the known 21-(acetyloxy)-6beta-fluoro-5alpha,11alpha,17-trihydroxypregnane-3,20-dione (13). Successive reaction with hypobromous acid, epoxidation, and fluorination converted 24a and 24b into the title compound 27a and the analogue 2-bromo compound 27b. In addition, a synthesis of 17,21-bis(acetyloxy)-2-chloro-6beta,9-difluoropregna-1,4-diene-3,20-dione (27c) is reported. The antiinflammatory activity of 17,21-bis-(acetyloxy)-6beta,9-difluoropregna-1,4-diene-3,20-dione (27a) and its 2-halogenated analogues 27b and 27c in comparison with the corresponding 6alpha,9-difluoro epimers was studied. Some 6beta-fluoro compounds displayed high topical antiinflammatory activity without systemic effects.

Topical steroid depression of the hypothalamic-pituitary-adrenal axis in psoriasis vulgaris.

Significant suppression of the hypothalamic-pituitary-adrenal axis has been found in patients hospitalized with psoriasis vulgaris and receiving topical fluorinated steroid therapy. Depression of thyroid function and involvement of autoimmune processes is also suggested by the data.

Endocrine effects of two new retro-steroids in animal models and in women.

PIP: Endocrine effects of 2 new retrosteroids, DU 164 and DU 41 165, in a nimal models and in women are reported. Both retrosteroids exhibited hi gh progestational activity in the rabbit, their potency being 18 times that of the reference standard, chlormadinone acetate (CMA), when administered orally. Both retrosteroids maintained pregnancy in rabbits and rats with a potency of 6 and 11 times that of CMA for DU 41 164 and DU 41 165, respectively. In the pregnancy maintenance tests in rats the effective dose (ED) 50 of DU 41 164 and DU 41 165 was 2000 mcg/kg/day and 290 mcg/kg/day, respectively, whereas CMA could not maintain pregnancy in doses of 50,000 mcg/kg/day. Both retrosteroids were highly active as antifertility agents in rabbits and rats. Their potencies were 80 and 40 times that of CMA in rabbits and 100 and 300 times that of CMA in rats. In ovulation inhibition tests the ED 50 of oral DU 41 164 and DU 41 165 were .5 and .4 mcg/kg in rabbits, whereas the ED 50 of CMA was 40 mcg/kg. The retrosteroids were also more potent than CMA in ovulation inhibition and antiestrogenic activity. High doses of DU 41 165 induced a decrease in adrenal weight and exhibited some antiinflammatory effects. 23 volunteers treated with 50 or 200 mcg of the compounds/day revealed no consistent inhibition of ovulation and of corpus luteum function. Endometrial biopsy specimens obtained on Cycle Days 12-13 during treatment with 200 mcg of either retrosteroid revealed no signs of progestational effect.^ieng

[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)]. / Untersuchungen zur Pharmakologie von 6alpha,9-Difluor-11beta-hydroxy-16-methyl-21-valeryloxy-1,40pregnadien-3,20-dion(Diflucortolonvalerianat)

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.

[Systemic effect of diflucortolone valerate after dermal application (author's transl)]. / Systemische Wirkung von Diflucortolonvalerianat nach dermaler Applikation

The systemic effect of 6alpha,9-difluor-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) 0.1% as an ointment and fatty ointment was investigated in two studies. The parameters used were the plasma 11-OHCS values and the urinary 17-OHCS and 17-KS values, respectively. Suppression of the plasma cortisol values was observed after topical application of both diflucortolone valerate and betamethasone-17-valerate to healthy subjects under extreme conditions of whole-body occlusion. However, it was still possible to stimulate the adrenal cortex with ACTH. No reduction of the 17-OHCS of 17-KS values in the 24-h urine was observed during open, large-surface treatment of patients with skin diseases.

[Efficacy of diflucortolone valerate in the vasoconstriction tests]. / Wirksamkeit von Diflucortolonvalerianat im Vasokonstriktionstest

The efficacy of a new topical corticosteroid, 6alpha,9-difluor-11beta-hylerate, Nerisona), as a 0.1% cream, ointment and fatty ointment was investigated in the vasoconstriction test in two series of studies after application to human skin in which hyperaemia had been experimentally induced. The diflucortolone valerate W/O emulsion proved to be 100 times more effective than fluocortolone in an identical base. In a further study diflucortolone valerate as well as in the three preparations was compared with nine known corticosteroids or their commercial preparations. In the comparison of the preparations only the cream with 0.05% betamethasone-17,21-dipropionate was superior to the diflucortolone valerate cream. As regards all the other preparations of formulations the new substance proved to be more or at least equally effective.

Vasoconstrictor activities of some novel synthetic steroids in alcoholic solution.

Ethanolic solutions of 8 new, topically active, anti-inflammatory steroids and 1 standard (betamethasone 17-valerate) were assessed with a modified vascoconstrictor assay. Pallor was graded at 17 reading times for determination of complete blanching curves. The compounds were ranked by three methods: (1) summed % total possible score, (2) area under the blanching profile, and (3) square root transformation of sum of scores divided by number of volunteers, for statistical differentiation of the solutions. Conclusions on structure-vasoconstrictor activity relationships were that substitution or removal of 21 hydroxy provided compounds with a wide range of activity. Poor activity correlated with a hemisuccinate salt grouping at position 21, or the absence of 11beta-hydroxy.