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PubMed1997

Synthesis and in vitro study of 17 beta-[N-ureylene-N,N'-disubstituted]-4-methyl-4-aza-5 alpha-androstan-3-ones as selective inhibitors of type I 5 alpha-reductase.

A series of 17 beta-(N-ureylene-N,N'-disubstituted)-4-azasteroids as inhibitors of human type I 5 alpha-reductase (5 alpha-Re) were prepared from 17 beta-N-alkyl-4-methyl-4-aza-5 alpha-androstan-3-ones and various isocyanates. For the measurement of 5 alpha-Re activity, 293 cells transfected with human type I 5 alpha-Re, cDNA were used. Azasteroids with an N-cyclopropyl ring exhibited potent inhibitory activity against type I 5 alpha-Re. As the chain length increased, from the N'-ethyl to the N'-butyl chain, activity of compounds also increased and azasteroids with the N'-butyl chain showed strong inhibitory activity (IC50 = 5.3 nM). Branching of alkyl chains decreased the potency of compounds. Introduction of the 1,2-double bond significantly reduced the activity of azasteroids. Replacement of the N'-alkyl chain with the phenyl moiety gave the most active compound of this series (IC50 = 1.3 nM). Other variations such as the replacement of a N-cyclopropyl ring with the N-methyl or the N-butyl chain decreased the activity of compounds (compounds were less active compared with above). The IC50 values of N-methyl-N'-cyclohexyl- and N-butyl-N'-phenyl-ureylenes were 31.5 and 11.5 nM. respectively. In general, all azasteroids were poor inhibitors of Type II 5 alpha-Re.

5-alpha Reductase Inhibitors↗
PubMed1995

Synthesis and in vitro activity of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-4-methyl-4-aza-3-oxo-5 alpha-androstan-3-ones as inhibitors of human 5 alpha-reductases and antagonists of the androgen receptor.

A number of 17 beta-(N-alkyl/arylformamido)- and 17 beta-[(N-alkyl/aryl)alkyl/arylamido]-3-oxo-4-aza-5 alpha-steroids were prepared from 17 beta-hydroxy-4-azasteroids and evaluated as inhibitors of human 5 alpha-reductase and antagonists of the androgen receptor. Jones' oxidation of 17 beta-hydroxy compounds gave the 17-keto-4-azasteroids, which were treated with amines and NaBH(OAc)3/NaBH3CN to give 17 beta-(N-alkyl/arylamino)-4-azasteroids 10-27. Alternatively, the above-indicated compounds were prepared from amines and 17-keto-4-azasteroids to form imines, which were then reduced with NaBH4. Formylation of amines 10-27 gave 17 beta-(N-alkylformamides) 28-41; however, acylation afforded 17 beta-[(N-alkyl/aryl)alkyl/arylamides] 42-53. In comparison to N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; IC50 = 4.15 nM), 17 beta-(N-alkylformamido)-4-azasteroids were potent inhibitors of human type I 5 alpha-reductase, IC50 values of compounds 29, 30, 36, and 37 being measured as 3.05, 0.91, 2.19, and 2.35 nM, respectively. The structure-activity relationships suggest that the type I enzyme has preference for N-substituted straight alkyl side chains of four to five carbon atoms. On the other hand, formamides 32 (N-heptyl) and 33 (N-octyl), in addition to inhibiting the type I enzyme (IC50s = 9.57 and 16.9 nM, respectively), showed also strong inhibitory activity (IC50s = 14.0 and 18.4 nM, respectively) for human type II 5 alpha-reductase, in comparison to N-(1',1'-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (MK-906; IC50 = 4.53 nM). Other compounds in this series showed moderate activities (IC50 > 100 nM) on the type II enzyme. 17 beta-[(N-Alkyl/aryl)alkyl/arylamides] 45, 46, 48, and 51 exhibited highly potent inhibitory activity for human type I 5 alpha-reductase with IC50s of 1.77, 2.42, 2.93, and 5.44 nM, respectively, while moderate to no effect was observed on the type II enzyme (100 < IC50s < 1000 nM), except for compound 48 (IC50 = 3.75 nM). In another substitution pattern, N-aryl/alkylamides were studied; an electron-donating group increased the potency of compound 51, whereas an electron-withdrawing group decreased the potency of compounds 52 and 53 compared to parent compound 50. In addition to their 5 alpha-reductase activities, 17 beta-(N-alkylformamides) were also studied for their inhibitory activities on dihydrotestosterone (DHT)-stimulated proliferation of androgen-sensitive Shionogi mouse mammary carcinoma cells (clone SEM-107).(ABSTRACT TRUNCATED AT 400 WORDS)

Androgen Receptor Antagonists↗
PubMed1985

Species differences in prostatic steroid 5 alpha-reductases of rat, dog, and human.

The conversion of testosterone to 5 alpha-dihydrotestosterone by prostate particulates from rats, dogs, and humans was investigated, and significant species differences were found with their pH profiles, affinities for 4-azasteroidal inhibitors, and sensitivities to mercuric sulfhydryl reagents. The pH optima for the rat (pH 7), the dog (pH 6), and the human (pH 5) enzyme are significantly different. Mersalyl acid and p-hydroxymercuribenzoate inactivate only the rat 5 alpha-reductase, but not the human or dog enzyme. The rank orders of potencies of 24 3-oxo-4-azasteroids to inhibit 5 alpha-reductases of the rat, dog, and human prostate are different. The variation of the 17 beta-functional groups of the inhibitors demonstrates clearly the species differences. Those inhibitors with a 17 beta-diethylcarbamoyl, 17 beta-diisopropylcarbamoyl, 17 beta-t-butylcarbamoyl, or 17 beta-secbutylcarbonyl functional group are approximately equipotent as inhibitors of the rat and human enzymes, whereas they are only 0.1-15% as potent as inhibitors of the dog enzyme. On the other hand, those inhibitors with a 17 beta-spiroether functional group are most potent as inhibitors of the rat enzyme, are 15-50% as potent as inhibitors of the dog enzyme, and are 0.2-0.4% as potent as inhibitors of the human enzyme. Those inhibitors with a 17 beta-n-octylcarbamoyl, 17 beta-(1-carboxyethyl), or 17 beta-(1-carboxy-3-butyl) functional group are 2-3 orders of magnitude less potent as inhibitors of the dog and human enzymes than as inhibitors of the rat enzyme. These results suggest that prostatic 5 alpha-reductases of rats, dogs, and humans are significantly different. In spite of the significant species differences in inhibitor affinities, where determined, inhibition of the rat, dog and human enzymes by these compounds is competitive with testosterone. These 3-oxo-4-azasteroids have a similar rank order of potency as inhibitors of 5 alpha-reductase in human normal, benign hyperplastic, and cancerous prostates, indicating that the inhibitor-binding sites of 5 alpha-reductase in the prostate in different pathological states are similar. The affinities of the 3-oxo-4-azasteroids for rat prostatic cytosol receptor were determined. Five of these 5 alpha-reductase inhibitors have no significant affinity for the androgen receptor, whereas others do have an affinity for the receptor.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMedDate not supplied

5 alpha-reductase inhibitors, chemical and clinical models.

An active site model of 5 alpha-reductase type 2 isoenzyme on an "active-analog approach" and based on 4-azasteroidal inhibitors has been constructed to evaluate the effects on the inhibitory potency of substituents on the steroid A ring. This model has proven able to predict the potential inhibitory activity of 19-nor-10-azasteroid and 6-azasteroid compounds. A model for the evaluation of clinical efficacy of an inhibitor, based on in vitro data, has also been developed and applied to finasteride. This inhibitory potency evaluation of finasteride in human scalp homogenates, plus pharmacokinetic data, allows the calculation of a theoretical in situ inhibition value for human scalp. From the IC50 curve of finasteride in scalp homogenates, it is possible to calculate that for an inhibition level similar to that obtained in prostate with 5 mg of finasteride, the necessary plasma concentration of the drug is 1 microM, a level obtained after the acute administration of 50 mg of finasteride.

Cholestenone 5 alpha-Reductase↗
PubMed1976

Structure-function activity of azasterols and nitrogen-containing steroids.

Thirty-nine nitrogen-containing steroids were tested against two gram-negative, five gram-positive, and two yeast organisms. Many of these steroids have been previously reported to inhibit various metabolic processes involving sterol metabolism. While low minimal inhibitory concentration (MIC) values were recorded for sterol producing yeast, growth of bacteria which contain no sterols was also inhibited. Structure-function studies provided no relationship between biological activity and hypocholesteremic effects of these azasteroids. A hypothesis put forward is that amino and azasteroids are effectors of membrane which, in the case of mitochondria, lead to changes in adenosine triphosphate levels and/or dehydrogenase activity. Their effects on sterol metabolism, therefore, may be of secondary consideration.

Androgens↗
PubMedDate not supplied

[Immunopharmacologic properties of 12-iminosubstituted 8-aza-D-homogonan and trimezon].

The immunopharmacological properties of two new compounds with an 8-azasteroidal structure, representing the salts (hydrochloride and acetate) of 12-imino-substituted 8-aza-D-homogonan, were studied in comparison with the properties of the immunostimulant trimeson. Similar to trimeson, both new compounds produce a dose-dependent activation of the humoral chain of immunogenesis in the model of primary immune response to goat erythrocytes in CBA, C57BL/6, and C57W mice. The immunostimulant activity of the 8-aza-D-homogonan derivatives is inversely proportional to the antigen load (2 x 10(7)-2 x 10(9) goat erythrocytes per mice) and depends to a considerable extent of the genotype of experimental animals. A modification of the 8-aza-D-homogonan structure by substituting imino group for oxygen at position 12 of the 8-azasteroidal skeleton leads to a sharp increase in toxicity as compared to that of trimeson.

Adjuvants, Immunologic↗
PubMed1986

Prostatic effects induced in dogs by chronic or acute oral administration of 5 alpha-reductase inhibitors.

A series of 4-azasteroidal 5 alpha-reductase inhibitors was tested in dogs to determine the effect of chronic (35-44 day) oral administration on prostate size and histology and acute oral administration on prostatic concentrations of testosterone (T) and dihydrotestosterone (DHT). The extent to which the results of the two tests were correlated was also studied in order to see whether the acute test could be used to predict activity in the chronic test. Six delta 1 analogs of the potent 5 alpha-reductase inhibitor, 4-MA (17 beta-N,N-diethylcarbamoyl-4-aza-4-methyl-5 alpha-androstan-3-one) were uniformly active at low dosage levels (less than or equal to 3 mg/kg) in both types of assay whereas several C1-C2 saturated analogs exhibited little activity in the chronic test. The nature of the side chain and whether there was a methyl or a proton at 4-N did not dramatically influence the activity of delta 1 compounds. There was a broad general agreement between the results of the two kinds of test in that if a compound acutely decreased the prostatic concentration of DHT it was likely to reduce prostate size and alter prostatic histology when given on a chronic basis.

5-alpha Reductase Inhibitors↗
PubMed1991

Hormonal effects, tolerability, and preliminary kinetics in men of MK-906, a 5 alpha-reductase inhibitor.

The hormonal effects following the acute (single dose) administration of a 4-azasteroid inhibitor of 5 alpha-reductase (MK-906) were evaluated in 10 healthy male volunteers. Marked suppression of serum dihydrotestosterone (DHT) was observed after the administration of single doses as low as 12.5 mg. The mean percent decrease in DHT at 24 hours in the group treated with a single 25-mg dose was 56% +/- 10% compared with the baseline. The suppression of plasma DHT levels continued for up to 72 hours. This study demonstrates that administration of single oral doses (12.5 to 400 mg) of MK-906 results in a significant decrease in the conversion of testosterone to DHT.

5-alpha Reductase Inhibitors↗
PubMed1994

Effects of 4-MA, a potent inhibitor of 5 alpha-reductase, on 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase activity in guinea pig adrenals.

Previous reports have shown that 17 beta-N,N-Diethylcarbamoyl-4-methyl-4-aza- 5 alpha-androstan-3-one (4-MA), a synthetic inhibitor of 5 alpha-reductase, exerts an inhibitory effect on 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) activity. To characterize further the effects of 4-MA on steroidogenesis, guinea pig fasciculata-glomerulosa cells in primary culture were treated for 24 h with 4-MA. Our data indicate that 4-MA reduced 3 beta-HSD activity in cultured adrenal cells but had no effect on the activities of 11-hydroxylase, 21-hydroxylase, 17-hydroxylase, and 17,20-lyase. Be decreasing the conversion of pregnenolone into progesterone or 17-hydroxypregnenolone into 17-hydroxyprogesterone, 4-MA caused the steroidogenic pathway to shift toward the production of dehydroepiandrosterone. Despite the presence of 4-MA, androstenedione and 11 beta-hydroxyandrostenedione were produced at levels exceeding the control levels. In the presence of ACTH and 4-MA, cortisol production was inhibited by 90% whereas androstenedione and 11 beta-hydroxyandrostenedione were reduced by only 40%. The effect of the compound was reversed by washing the adrenal cells with medium, thus suggesting a direct action of 4-MA on the enzyme itself. In summary, our data indicate that 4-MA markedly reduces the production of cortisol in the adrenals and partially alters the formation of C-19 steroids. It is important to consider this finding in the use of 4-azasteroids in the treatment of prostate cancer, which was previously found to be sensitive to secretion of adrenal C-19 steroids.

Androgen Antagonists↗
PubMed1994

Novel aromatase and 5 alpha-reductase inhibitors.

Inhibitors of aromatase and 5 alpha-reductase may be of use for the therapy of postmenopausal breast cancer and benign prostatic hyperplasia, respectively. FCE 27993 is a novel steroidal irreversible aromatase inhibitor structurally related to exemestane (FCE 24304). The compound was found to be a very potent competitive inhibitor of human placental aromatase, with a Ki of 7.2 nM (4.3 nM for exemestane). In preincubation studies with placental aromatase FCE 27993, like exemestane, was found to cause time-dependent inhibition with a higher rate of inactivation (t1/2 4.5 vs 15.1 min) and a similar Ki(inact) (56 vs 66 nM). The compound was found to have a very low binding affinity to the androgen receptor (RBA 0.09% of dihydrotestosterone) and, in contrast to exemestane, no androgenic activity up to 100 mg/kg/day s.c. in immature castrated rats. Among a series of novel 4-azasteroids with fluoro-substituted-17 beta-amidic side chains, three compounds, namely FCE 28260, FCE 28175 and FCE 27837, were identified as potent in vitro and in vivo inhibitors of prostatic 5 alpha-reductase. Their IC50 values were found to be 16, 38 and 51 nM for the inhibition of the human enzyme, and 15, 20 and 60 nM for the inhibition of the rat enzyme, respectively. When given orally for 7 days in castrated and testosterone (Silastic implants) supplemented rats, the new compounds were very effective in reducing prostate growth. At a dose of 0.3 mg/kg/day inhibitions of 42, 36 and 41% were caused by FCE 28260, FCE 28175 and FCE 27837, respectively.

5-alpha Reductase Inhibitors↗
PubMed1995

Human prostatic steroid 5 alpha-reductase isoforms--a comparative study of selective inhibitors.

The present study describes the independent expression of the type 1 and 2 isoforms of human 5 alpha-reductase in the baculovirus-directed insect cell expression system and the selectivity of their inhibition. The catalytic properties and kinetic parameters of the recombinant isozymes were consistent with published data. The type 1 isoform displayed a neutral (range 6-8) pH optimum and the type 2 isoform an acidic (5-6) pH optimum. The type 2 isoform had higher affinity for testosterone than did the type 1 isoform (Km = 0.5 and 2.9 microM, respectively). Finasteride and turosteride were selective inhibitors of the type 2 isoform (Ki (type 2) = 7.3 and 21.7 nM compared to Ki (type 1) = 108 and 330 nM, respectively). 4-MA and the lipido-sterol extract of Serenoa repens (LSESr) markedly inhibited both isozymes (Ki (type 1) = 8.4 nM and 7.2 micrograms/ml, respectively; Ki (type 2) = 7.4 nM and 4.9 micrograms/ml, respectively). The three azasteroids were competitive inhibitors vs substrate, whereas LSESr displayed non-competitive inhibition of the type 1 isozyme and uncompetitive inhibition of the type 2 isozyme. These observations suggest that the lipid component of LSESr might be responsible for its inhibitory effect by modulating the membrane environment of 5 alpha-reductase. Partially purified recombinant 5 alpha-reductase type 1 activity was preserved by the presence of lipids indicating that lipids can exert either stimulatory or inhibitory effects on human 5 alpha-reductase.

Animals↗
PubMed2004

Expression of cytochrome P450c17 and other steroid-converting enzymes in the rat kidney throughout the life-span.

We have investigated the metabolism of [14C]-labelled progesterone (P4) and dehydroepiandrosterone (DHEA) by kidney tissues of newborn and 7-, 15-, 30-, 60- and 365-day-old rats of both sexes. The following enzymes were revealed at all ages by radiochemical identification of the corresponding products: 5alpha-reductase, cytochromes P450c17 and P450c21, 3beta-hydroxysteroid dehydrogenase (HSD)/delta5-delta4 isomerase, and 17beta- and 20alpha-HSDs, catalyzing reductive reactions. The major P4 metabolites were 5alpha-reduced C21 steroids, whose formation was almost completely suppressed by the 5alpha-reductase 4-azasteroid inhibitor, PNU 156765. Androstenedione and testosterone were also formed via 17alpha-hydroxyprogesterone, together with 11-deoxycorticosterone and 20alpha-dihydroprogesterone. DHEA was mainly converted to androst-5-ene-3beta,17beta-diol, with smaller amounts of the above androgens. Cytochrome P450c17 mRNA and protein were demonstrated by Northern blotting and Western blotting analyses, respectively. P450c17 mRNA, assessed by Northern blotting, protein and catalytic activity all peaked in the kidney samples at 15 days of life and declined thereafter. Cytochrome P450arom was below the level of detection of semi-quantitative RT-PCR. Since the rat kidney has been previously shown to contain cytochrome P450scc as well as androgen and estrogen receptors, it is suggested that it is capable of autonomous hormonal steroidogenesis and that renal steroids, or nephrosteroids, may act locally, in a paracrine or autocrine fashion.

3-Hydroxysteroid Dehydrogenases↗