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At least 19 recordsLinked to original sources
PubMed1997

19-nor-10-azasteroids, a new class of steroid 5 alpha-reductase inhibitors. 2. X-ray structure, molecular modeling, conformational analysis of 19-nor-10-azasteroids and comparison with 4-azasteroids and 6-azasteroids.

19-Nor-10-azasteroids are a new class of 5 alpha-reductase inhibitors whose activity depends on the presence of the bridgehead N-10 atom conjugated with the 4-en-3-one moiety in the A ring. The X-ray structure of 19-nor-10-azasteroid 1 has been determined and it is compared with the X-ray structure of testosterone. A complete conformational analysis of these compounds has been performed, determining the number and energy of the possible conformers, as well as the molecular flexibility of the 10-azasteroidal skeleton. Thus, MM2* molecular mechanics calculations and AM1 semiempirical energy refinements revealed that 19-nor-10-azasteroids 1-3 have four possible conformations with very small energy differences and that they are very flexible molecules. The conformational analysis has been extended to testosterone (4), which also showed conformational flexibility, with three different conformations, and to 6-azasteroid 5 and 4-azasteroid 6, for which only two thermally accessible conformations have been found. Compared to 19-nor-10-azasteroids 1-3, azasteroids 5 and 6 appear to be more rigid structures. By a best fit analysis of all conformers of 1-5 with the global minimum of testosterone (4-I) it has been found that the lowest energy conformers of 1, 3, and 5 are very close to the structure of 4-I, and among the conformers of 2, the best similarity has been observed for the highest energy conformer 2-IV.

5-alpha Reductase Inhibitors↗
PubMed1976

15-Azasteroid blockage of cell permeability and mitochondrial respiration.

The 15-azasteroid, 1,10,11,11a-tetrahydro-11a-methyl-2H naphth (1,2-g)indol-7-o1, inhibits the growth of the cell culture lines KB and L-M as well as several strains of bacteria. The inhibition of growth is reversed following removal of the steroid from the growth medium. Using in vitro grown L-M cells, the compound inhibited the transport of amino acids and uracil. The action was non-detergent like and at least 100 times more effective in terminating metabolite transport than sodium azide. The azasteroid inhibited the oxidation of glutamate in isolated rat liver mitochondria. The oxidation of succinate was not effected by the azasteroid alone but in the presence of glutamate, the azasteroid uncoupled the oxidation of succinate from the ADP-ATP control. It is suggested that the azasteroid may be acting directly on the electron transport system and/or acting indirectly through membrane perturbations which disrupts the electron transport process.

Alanine↗
PubMed1984

Effects of azasteroids on growth and development of the free-living stages of Nippostrongylus brasiliensis and Nematospiroides dubius.

25-Azasteroids were evaluated for their effects on the growth and development of the free-living stages of Nippostrongylus brasiliensis and Nematospiroides dubius. Increasing the concentration of 25-azasteroids in axenic cultures of either species resulted in a decrease in the percentage and mean length of larvae that developed to the third stage. Morphologic abnormalities of inhibited larvae were similar to those shown by larvae cultured in sterol-deficient medium. Addition of cholesterol to the culture medium reversed the inhibitive effects of azasteroid. Azasteroid completely inhibited growth and development of N. brasiliensis when the only sterol present in the culture medium was sitosterol. These results suggest similar pathways of sterol metabolism and similar mechanisms of action by azasteroids in the nematodes and insects that have been studied.

Animals↗
PubMed1985

Effects of an azasteroid on growth, development and reproduction of the free-living nematodes Caenorhabditis briggsae and Panagrellus redivivus.

The azasteroid, 25-azacoprostane (ASA-6), was evaluated for its effects on the growth, development and reproduction of the free-living nematodes, Caenorhabditis briggsae and Panagrellus redivivus. The axenic culture medium for either species of nematode consisted of Caenorhabditis briggsae Maintenance Medium (CbMM): formalin-killed Escherichia coli (1:1) with or without the addition of 5 micrograms cholesterol per ml and/or 25 micrograms ASA-6 per ml medium. All cultures also contained 50 micrograms Tween 80 per ml medium. After two generations of growth in sterol-deficient media, both species displayed a decrease in mean length, a decrease in the percent development to the adult stage and an inhibition of reproductive capability. These effects were more apparent in the sterol-deficient medium containing ASA-6. In the presence of cholesterol and ASA-6, growth and reproduction of C. briggsae, but not of P. redivivus, was inhibited after five generations. Morphologic abnormalities of azasteroid-inhibited worms were similar to those shown by worms cultured in sterol-deficient medium. These results suggest that different species of nematodes may exhibit different responses to azasteroid and that sterol utilization and metabolism may vary between nematode species. In addition, the similarities between the known effects of azasteroid inhibition in insects and those presented in this study on nematodes suggest a similar mechanism of action by the inhibitor in both groups of organisms.

Animals↗
PubMed1986

Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding.

A series of steroids, primarily 4-azasteroids, were prepared and tested in vitro as inhibitors of human and rat prostatic 5 alpha-reductase and of binding of dihydrotestosterone to the rat androgen receptor. The primary structural modifications were changes of the A ring and of moieties attached at the C-17 position of the steroid nucleus. New A-ring modifications included the 4-cyano-3-oxo-delta 4 system in the carbocyclic series and 1 alpha-CN, 1 alpha-CH3, 1 alpha,2 alpha-CH2, 2 beta-F, 2-aza, 2-oxa, and A-homo changes in the 3-oxo-4-aza series. In addition, 4-azasteroids with a D-homo ring or methyl substitution at C-7 (alpha and beta) or C-16 (alpha and beta) were prepared. The majority of the C-17 substituents were prepared from reactive intermediates derived from the 17 beta-COOH. Enhanced 5 alpha-reductase inhibition in both the human and rat enzyme assays is seen with 4-CN substitution on 3-oxo-delta 4 steroids and with a C-17 side chain incorporating a lipophilically substituted semipolar group on the 4-aza-3-oxo-5 alpha-androstane nucleus. Fewer highly active compounds were found in the human enzyme assay than in the rat assay. Structural requirements for inhibition of the rat androgen receptor are much different from those for inhibition of the enzyme. The 17 beta-OH moiety enhances potency more than any other feature while introduction of double bonds at C-1 or C-5 in the azasteroid gives a small improvement. Azasteroids unsubstituted at the 4-position show greatly diminished receptor activity.

5-alpha Reductase Inhibitors↗
PubMed1984

Azasteroids as inhibitors of rat prostatic 5 alpha-reductase.

A series of A-ring heterocyclic steroids has been prepared and tested for inhibition of rat prostatic steroid 5 alpha-reductase in vitro. Strikingly high inhibitory activity was found with a group of 17 beta-substituted 4-methyl-4-aza-5 alpha-androstan-3-ones. These compounds were prepared from 3-keto-delta 4-precursors by oxidative (O3 or NaIO4-KMnO4) A-ring cleavage followed, in turn, by ring closure with an amine and hydrogenation over platinum catalyst. Other A-ring azasteroids were made by Beckmann rearrangement of oximes of 2-oxo-A-nor, 3-oxo- and 4-oxo-5 alpha-androstanes. An A-nor-2-oxo-3-azasteroid was prepared by oxidative decarbonylation of a precursor 2,3-dioxo-4-azasteroid with m-chloroperbenzoic acid. A-ring modifications of the 4-azasteroids included delta 1-unsaturation, 2- and 4-substituents, and 3-carbonyl replacements. Side chains at the 17-position were varied with an emphasis on carboxylate derivatives (salts, esters, and amides).

5-alpha Reductase Inhibitors↗
PubMed1995

Comparison of the effects of new specific azasteroid inhibitors of steroid 5 alpha-reductase on canine hyperplastic prostate: suppression of prostatic DHT correlated with prostate regression.

Four new azasteroid inhibitors of steroid 5 alpha-reductase were compared to the benchmark compound finasteride, each at a dose level of 1 mg/kg/day, as well to placebo and to castration, in seven groups of mature male beagle dogs with enlarged prostates. Prostate volumes were measured repetitively by a volume MRI method over 15 weeks of treatment. The study probed the obverse of the familiar relation between DHT and prostate growth, and provides the first documentation of a tight negative correlation between prostate regression and the prostatic concentration of DHT across a range of treatment regimens (r = -0.982). In this first direct comparison study of structure vs. in vivo activity for several azasteroids in the dog model of BPH, relative efficacy for induction of shrinkage of the dog prostate did not correlate at all with the inhibitor's relative activity against the dog 5 alpha-reductase in vitro. On the basis of the relative IC50 values it would not have been predicted that, at the dose tested, the analogue MK-434 (17 beta-benzoyl-4-aza-5 alpha-androst-1-en-3-one) was distinguished from the other inhibitors with respect to the induction of faster and more complete regression (69%) as well as greater reduction in prostatic DHT (95%), both of which approached the castrated dog levels of 75% prostatic shrinkage and > 98% reduction in DHT. Treatment with any one of the five azasteroids induced two- to five-fold increases in prostatic testosterone. However, total androgen was conserved at the placebo control level. Despite the differences noted, each azasteroid tested induced a highly significant decrease in prostatic volume that correlated tightly with a decreased prostatic DHT level in canine spontaneous BPH.

5-alpha Reductase Inhibitors↗
PubMed1976

Antibacterial activity of 15-azasteroids alone and in combination with antibiotics.

A new class of 15-azasteroid analogues has been synthesized and tested for antimicrobial activity. The compounds 1, 10, 11, 11a-tetrahydro-7-methoxy-11a-methyl-2H-naphth (1,2-g) indol (methoxyimine) and 1,10,11,11a-tetrahydro-11a-methyl-2H-naphth (1,2-g) indol-7-ol (hydroxyimine) inhibit the growth of Bacillus subtillis and Escherichia coli at concentrations as low as 10-5 M. Addition of either compound to the growth medium casued a rapid inhibition in the transport of radioactive glucose, uracil and several amino acids. The inhibition of growth and substrate transport was reversed following removl of the steroid from the medium. The evidence is consistent with a site of steroid action at the cell periphery. Combining the methoxyimine with polyor circulin at subinhibitory concentrations produced greatly enhanced antimicrobial activity against Pseudomonas fluorescens. Similar action was observed against B. subtilis when the azasteroid was combined with vancomycin or chloramphenicol. The inhibitory action of other antibiotics such as penicillin or erythromycin was not affected by addition of the test compound. The results suggest formation of a molecular complex between the azasteroid and antibiotic which is responsible for the enhanced biological activity.

Aminoisobutyric Acids↗
PubMed1993

Azasteroids as inhibitors of testosterone 5 alpha-reductase in mammalian skin.

Elevated levels of testosterone 5 alpha-reductase (5 alpha-R) and its product, dihydrotestosterone are associated with a number of androgen-dependent skin conditions. A series of 4-azasteroids were tested in vitro as inhibitors of 5 alpha-R in the isolated anagen human hair follicle. Major structural requirements for maximal 5 alpha-R inhibitory activity include a 4-methyl-4-aza moiety and a bulky, lipophilic side chain at C-17. Only one compound, 17 beta-N,N-diethylcarbamyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), was found to be a potent 5 alpha-R inhibitor in all tissues studied: human hair follicles, foreskin (Ki = 3 nM), genital fibroblasts (Ki = 12 nM), and prostate. 17 beta-Hydroxysteroid dehydrogenase activity was not inhibited by 4-MA. With the exception of 4-MA, azasteroid IC50s varied widely in human prostate vs skin, suggesting the possible existence in man of at least two 5 alpha-R isozymes. Finasteride [N(1,1-dimethylethyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide], a delta 1 orally active, specific 5 alpha-R inhibitor exhibiting no affinity for the androgen receptor, was only modestly active in the hair follicle microassay (IC50 = 200 nM). However, it was a potent in vitro inhibitor of human foreskin and prostate 5 alpha-R. Orally administered to rats finasteride inhibited 5 alpha-R in skin. A vasodilator used to treat male pattern baldness (MPB), minoxidil, was found to be a weak inhibitor of human hair follicle 5 alpha-R (IC50 = 1000 nM). 5 alpha-R activity in frontal scalp hair follicles from a MPB subject was four times higher than in occipital follicles. 4-Azasteroids are efficient inhibitors of human skin 5 alpha-R and offer promise for the treatment of acne, hirsutism and MPB.

5-alpha Reductase Inhibitors↗
PubMed2002

13C-NMR study of 4-azasteroids in solution and solid state.

A group of biologically active 4-azasteroids was studied by 13C-NMR spectroscopy in solution and in the solid phase. A full assignment of signals in the spectra of samples in chloroform was performed for thirteen 4-azasteroids using two-dimensional techniques. Substituent and steric effects of a nitrogen atom, and their influence on chemical shifts of the neighboring carbon atoms are discussed. CP MAS spectra were obtained for five 4-azasteroids including finasteride. The spectra confirmed polymorphism of the latter compound. In addition to the polymorphic forms that are already known, a new molecular complex of finasteride with dioxane is reported.

Azasteroids↗
PubMed1997

19-nor-10-azasteroids: a novel class of inhibitors for human steroid 5alpha-reductases 1 and 2.

Steroid 5alpha-reductase is a system of two isozymes (5alphaR-1 and 5alphaR-2) which catalyzes the NADPH-dependent reduction of testosterone to dihydrotestosterone in many androgen sensitive tissues and which is related to several human endocrine diseases such as benign prostatic hyperplasia (BPH), prostatic cancer, acne, alopecia, pattern baldness in men and hirsutism in women. The discovery of new potent and selective 5alphaR inhibitors is thus of great interest for pharmaceutical treatment of these diseases. The synthesis of a novel class of inhibitors for human 5alphaR-1 and 5alphaR-2, having the 19-nor-10-azasteroid skeleton, is described. The inhibitory potency of the 19-nor-10-azasteroids was determined in homogenates of human hypertrophic prostates toward 5alphaR-2 and in DU-145 human prostatic adenocarcinoma cells toward 5alphaR-1, in comparison with finasteride (IC50 = 3 nM for 5alphaR-2 and approximately 42 nM for 5alphaR-1), a drug which is currently used for BPH treatment. The inhibition potency was dependent on the type of substituent at position 17 and on the presence and position of the unsaturation in the A and C rings. delta9(11)-19-Nor-10-azaandrost-4-ene-3,17-dione (or 10-azaestra-4,9(11)-diene-3,17-dione) (4a) and 19-nor-10-azaandrost-4-ene-3,17-dione (5) were weak inhibitors of 5alphaR-2 (IC50 = 4.6 and 4.4 microM, respectively) but more potent inhibitors of 5alphaR-1 (IC50 = 263 and 299 nM, respectively), whereas 19-nor-10-aza-5alpha-androstane-3,17-dione (7) was inactive for both the isoenzymes. The best result was achieved with the 9:1 mixture of delta9(11)- and delta8(9)-17beta-(N-tert-butylcarbamoyl)-19-nor-10-aza-4- androsten-3-one (10a,b) which was a good inhibitor of 5alphaR-1 and 5alphaR-2 (IC50 = 127 and 122 nM, respectively), with a potency very close to that of finasteride. The results of ab initio calculations suggest that the inhibition potency of 19-nor-10-azasteroids could be directly related to the nucleophilicity of the carbonyl group in the 3-position.

5-alpha Reductase Inhibitors↗
PubMed2001

Linear relationships between the ligand binding energy and the activation energy of time-dependent inhibition of steroid 5alpha-reductase by delta 1-4-azasteroids.

The inhibition of steroid 5alpha-reductase (5AR) by Delta(1)-4-azasteroids is characterized by a two-step time-dependent kinetic mechanism where inhibitor combines with enzyme in a fast equilibrium, defined by the inhibition constant K(i), to form an initial reversible enzyme-inhibitor complex, which subsequently undergoes a time-dependent chemical rearrangement, defined by the rate constant k(3), leading to the formation of an apparently irreversible, tight-binding enzyme-inhibitor complex (Tian, G., Mook, R. A., Jr., Moss, M. L., and Frye, S. V. (1995) Biochemistry 34, 13453-13459). A detailed kinetic analysis of this process with a series of Delta(1)-4-azasteroids having different C-17 substituents was performed to understand the relationships between the rate of time-dependent inhibition and the affinity of the time-dependent inhibitors for the enzyme. A linear correlation was observed between ln(1/K(i)), which is proportional to the ligand binding energy for the formation of the enzyme-inhibitor complex, and ln(1/(k(3)/K(i))), which is proportional to the activation energy for the inhibition reaction under the second order reaction condition, which leads to the formation of the irreversible, tight-binding enzyme-inhibitor complex. The coefficient of the correlation was -0.88 +/- 0.07 for type 1 5AR and -1.0 +/- 0.2 for type 2 5AR. In comparison, there was no obvious correlation between ln(1/K(i)) and ln(1/k(3)), which is proportional to the activation energy of the second, time-dependent step of the inhibition reaction. These data are consistent with a model where ligand binding energies provided at C-17 of Delta(1)-4-azasteroids is fully expressed to lower the activation energy of k(3)/K(i) with little perturbation of the energy barrier of the second, time-dependent step.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1981

Effects of branched and straight chain amines and azasteroids on blood and egg cholesterol of White Leghorn chickens.

Six branched and straight chain secondary or tertiary amines with chain lengths of 12 to 18 carbons and two azasteroids, 25-aza-5 alpha-cholestane and 25-azacoprostane, were fed to mature White Leghorn hens, and their effectiveness was compared with 20,25-diazacholesterol dihydrochloride (SC-12937), an azasteroid known to lower egg cholesterol. Feed consumption, body weight, egg production, egg and plasma cholesterol and desmosterol, and plasma total lipid were measured. The 6 amines were fed at 200 ppm, and only the C12 branched chain amine N,N,3,711-pentamethyldodecanamine reduced plasma and egg cholesterol with a concomitant increase in desmosterol. After 4 weeks, plasma desmosterol was 0, 13, 60, and 75% of total sterol for control, 200 ppm C12 branched chain amine, 5 ppm diazacholesterol, and 5 ppm azacholestane, respectively. Egg production was severely reduced to 6 and 0% by feeding 5 ppm azacholestane for 2 and 4 weeks, respectively, and to 69 and 36% by feeding 5 ppm diazacholesterol. After 4 weeks egg cholesterol was 79 and 36% of the total sterol for the 200 ppm C12 branched chain amine and 5 ppm diazacholesterol, respectively. Concomitant increases in desmosterol accompanied all reductions in cholesterol. The depletion and repletion rates of egg cholesterol were measured in a subsequent experiment. After 2-1/2 weeks of feeding the test substances, egg cholesterol was reduced with concomitant increases in desmosterol. Egg cholesterol was 100, 71, and 50% of the total egg sterol for control, 200 ppm, and 400 ppm C12 branched chain amine, respectively: 58, 13, and 3% for .1, .5, and 1.0 ppm azacholestane; 28, 29, and 18% for 1, 2.5, and 5 ppm azacholesterol; and 23% for 1 ppm azacoprostane. The experimental diets were then withdrawn, and egg cholesterol repletion was studied biweekly. Egg cholesterol was repleted to 100% of the total sterol after withdrawal times of 2 weeks for C12 branched chain amine, 8 weeks for azacoprpostane, 14 to 16 weeks for diazacholesterol, 10 to 16 weeks for the lower levels of azacholestane, and longer than 16 weeks for 1 ppm azacholestane. The increase in desmosterol accompaning the demonstrated reduction in egg cholesterol, particularly with azasteroids, causes one to question the usefulness of this approach to lower cholesterol.

Amines↗
PubMedDate not supplied

[The pharmacokinetics of an immunomodulator of the D-homo-8-azasteroid series].

The pharmacokinetic investigation and the study of metabolism of an immunostimulator of 8-azasteroid series were performed on a single-compartment model. The main pharmacokinetic parameters of the immunomodulator in mice were established using different routes of administration. The maximal accumulation of tritium-labeled 8-azasteroid was recorded in the kidneys, liver and lung. The character of distribution changes with time. The half-life period is in the range of from 0.69 to 1.4 hours at different routes of administration. The total clearance is 0.49 ml/min, the area under the pharmacokinetic curve--3.8-8.1 micrograms/h/ml. On the model of the monooxygenase cytochrome P-450-containing system of the liver microsomes there was confirmed the formation of two metabolites preliminarily isolated from the mouse urine. By the character of resorption, distribution, elimination this 8-azasteroid immunoactivator is close to the agents of glucocorticoid series.

Adjuvants, Immunologic↗
PubMed1975

Inhibitive effects of structurally modified azasteroids and related nitrogen containing steroids on insect growth and development.

A number of azasteroids and other nitrogen containing steroids with a modified nucleus or side chain were prepared and tested for their inhibitory effects on the growth and development of several species of insects. Structure-activity studies showed that compounds with a structurally related steroid nucleus and side chain were approximately equal in inhibitory activity for a particular species. The replacement of the tertiary amino group in the side chain of the 5beta-steroid with other nitrogen substituents, such as nitro, cyano, acetylamino, or a quaternary ammonium salt, resulted in a considerable loss of inhibitive activity in the tobacco hornworm or the yellowfever mosquito. However, certain modifications of the azasteroid nucleus resulted in compounds that still retained high biological activity. As a result, a compound was synthesized that lacked the A and B rings of the steroid nucleus and that inhibited insect growth, molting, and metamorphosis and the delta24-sterol reductase enzyme system of the tobacco hornworm.

Aedes↗
PubMed1986

5 Alpha-reductase inhibitory and anti-androgenic activities of some 4-azasteroids in the rat.

Inhibition of 5 alpha-reductase and anti-androgenicity were studied in rats treated with various 4-azasteroids. The known inhibitor, N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA) served as a reference compound, and analogs of this basic molecule were assayed. Enhancement of enzyme inhibitory potency was usually seen with delta 1 analogs, whereas reduction in activity was noted with substitutuents such as delta 5, a spirotetrahydrofuran ring at C-17 or 4-deaza groups. Many of the 4-azasteroids had a much greater oral anti-androgenic effect against testosterone propionate (TP) than dihydrotestosterone propionate (DHTP). This difference in activity versus the two androgens is believed to reflect the necessity for TP to undergo reduction to DHT before becoming capable of stimulating prostatic growth. Inhibition of 5 alpha-reductase by active compounds prevented the conversion, thereby producing an anti-androgenic effect. In this regard, certain delta 1 analogs of 4-MA, particularly those bearing a 17 beta-(N-tert butylcarbamoyl) group, proved very effective against TP but were relatively inactive versus DHTP.

Androgen Antagonists↗
PubMed1984

4-Azasteroidal 5 alpha-reductase inhibitors without affinity for the androgen receptor.

In efforts to develop potent 5 alpha-reductase inhibitors without affinity for the androgen receptor, synthetic 3-oxo-5 alpha-steroids were tested for their ability to inhibit 5 alpha-reductase, using [14C]testosterone as the substrate, and for their ability to inhibit the binding of [3H]5 alpha-dihydrotestosterone to the androgen receptor of rat prostate cytosol. 2',3' alpha-Tetrahydrofuran-2'-spiro-17-(5 alpha-androstan-3-one) is not an inhibitor of 5 alpha-reductase and has a high affinity for the androgen receptor; substitution of the -CH2- at the 4-position with N-H resulted in a good inhibitor of 5 alpha-reductase. The 4-N-CH3 derivative is even more active, whereas the N-CH2-CH3 derivative is inactive. These 4-aza derivatives have much lower affinity for the androgen receptor than the parent compound. The 4-N-H derivatives of several 3-oxo-5 alpha-steroids were found to be 20-100% as potent as their corresponding 4-N-CH3 analogs as inhibitors of 5 alpha-reductase, whereas their androgen receptor affinities were at least 40-fold lower than their 4-N-CH3 analogs. Their 5 beta-isomers did not inhibit either 5 alpha-reductase or the androgen receptor binding of [3H]5 alpha-dihydrotestosterone. Two of these 4-N-H steroids, 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one and 17 beta-N, N-diisopropylcarbamoyl-4-aza-5 alpha-androstan-3-one, are potent 5 alpha-reductase inhibitors with Ki values equal to 29.2 +/- 1.7 and 12.6 +/- 0.8 nM, respectively, but have little affinity for the androgen receptor. The inhibition of 5 alpha-reductase by both compounds is competitive with testosterone. When [3H]testosterone was incubated with minced rat prostate in the presence of either of these two 4-azasteroids, the nuclear concentration of 5 alpha-dihydrotestosterone decreased and that of testosterone increased. The total nuclear uptake of testosterone plus 5 alpha-dihydrotestosterone was not significantly affected. These 4-azasteroids should be useful for investigating the importance of 5 alpha-reductase in androgen action in vivo.

5-alpha Reductase Inhibitors↗
PubMed2001

Substrate interaction with 5alpha-reductase enzyme: influence of the 17beta-chain chirality in the mechanism of action of 4-azasteroid inhibitors.

A series of steroidal compounds were synthesized in order to evaluate the possible influence of the configuration of a stereocenter in the 17beta-side chain on the inhibitory activity on the enzyme 5alpha-reductase (5AR). For this purpose diastereomerically pure 4-azasteroids epimers at C-22 were prepared (compounds 1-11) and tested as inhibitors of 5AR in "in vitro" tests. The obtained data showed that in most cases the couples of epimers possess a significant difference in their biological activity. We also considered, for the tested molecules, a series of chemico-physical parameters in order to find a possible correlation with their biological activity. The findings allowed us to propose a model of the binding site of 5AR which comprises also, for 4-azasteroid inhibitors, the configurational aspect of the 17beta-side chain.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗