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PubMed1967

Effect of azasteroids on gram-positive bacteria.

A group of nitrogen-containing steroids closely related in structure was screened for antibacterial activity, by use of Bacillus subtilis and Sarcina lutea as the test organisms. The most active compounds were cholesterol derivatives containing a tertiary or quaternary nitrogen in, or attached to, the A ring. Similar methyltestosterone or progesterone derivatives were inactive. All of the cholesterol derivatives that inhibited growth were surfactant, and, structurally, they would be classified as cationic detergents. Some of the inactive compounds were surfactant, but, structurally, they would be classified as nonionic detergents. Certain features of the antibacterial activity of one of the active steroids-ND 212 (4-dimethylaminoethyl-4-aza-5-cholesten-3-one methiodide)-were studied. Growth of a culture of B. subtilis containing 5 x 10(7) cells per milliliter was inhibited by 1 mug/ml (1.7 x 10(-6)m) of ND 212. The amount of growth inhibition was directly related to both cell and steroid concentration. Loss of viability was rapid and irreversible. With B. subtilis, cell lysis was observed. With S. lutea grown in C(14)-glucose, ND 212 caused release into the media of up to 25% of the cellular radioactivity. Extensive leakage occurred before loss of viability was observed. At bacteriostatic azasteroid concentrations, there was little leakage. ND 212 was readily bound in large amounts to B. subtilis cells. Inactive azasteroids were bound poorly. C(14)-cholestanone was also bound, whereas C(14)-methyltestosterone and C(14)-progesterone were not bound in significant amounts. At least 50% of the bound C(14)-cholestanone was associated with the membrane fraction.

Bacillus subtilis↗
PubMed1989

Hormonal effects of an orally active 4-azasteroid inhibitor of 5 alpha-reductase in humans.

The objective of this study was to estimate the minimum in vivo effective oral dose and duration of action of the competitive 5 alpha-reductase inhibitor MK-906, a 4-azasteroid, in humans. Plasma dihydrotesterone (DHT), 5 alpha-androstane-3 alpha,17 beta-diol (AD), and its glucuronide (ADG), as well as urinary androsterone (A) and 5 alpha-pregnane-3 alpha,11 beta, 17 alpha,21-tetrol-20-one (aH4F) were determined in 54 healthy young men before and up to 7 days after a single morning dose of the compound. Twenty-four hours after a single 5- to 40-mg dose (n = 24), plasma DHT levels decreased by a mean of +/- 65%, with slow recovery of DHT levels. Seven days later, DHT remained decreased by +/- 15%. Plasma AD levels decreased to a similar degree, whereas ADG levels decreased by about 75%, indicating inhibition of target tissue 5 alpha-reductase. Testosterone levels did not show any significant variations. The A as well as aH4F excretion in the 24-hour urine test following drug administration decreased by 65%, indicating inhibition of the hepatic 5 alpha-reductase. After a single dose of 1.5 or 0.5 mg, DHT levels decreased by 50% 24 hours after administration, returning to normal within 5-7 days; at this dose, urinary A and aH4F excretion decreased by 50%. A single dose of 0.2 mg appeared to be slightly active as a 5 alpha-reductase inhibitor, but no statistically significant effect on DHT levels was observed after administration of a single 0.04-mg dose. It is concluded that MK-906 is a highly effective 5 alpha-reductase inhibitor in vivo. The effect on plasma DHT lasts for several days after administration of a single oral dose. The data suggest that both hepatic and extrasplanchnic 5 alpha-reductases are inhibited.

5-alpha Reductase Inhibitors↗
PubMed1994

N-alkylation of 17-azasteroids.

N-Alkylation of 17-azasteroid lactams (16-oxo-17-azaandrost-5-en-3 beta-ol acetate 3 and its D-homo analog 4) was studied. It has been found that both lactams are readily alkylated with iodomethane or iodoethane. In contrast to this there was no reaction with 2-iodo-6-methylheptane due to the steric hindrance. 1,4-Addition of lactam to the conjugated systems was also studied. The addition to acrylonitrile proved to be easy compared to crotononitrile. However the efficient addition to the latter compound was also attained by using potassium t-butoxide as a base in t-butanol.

Acrylonitrile↗
PubMed1995

Comparative study of SCE induction and cytostatic effects by homo-azasteroidal esters of N,N-bis(2-chloroethyl)aminobenzoic acid in human lymphocytes.

The effect of homo-azasteroidal esters of benzoic acid mustard isomers and the 4-methyl derivatives, which have steroidal lactams as a biological basis, on cytogenetic damage was studied. Twenty compounds were comparatively studied, on a molar basis, as regards their ability to induce sister-chromatid exchanges (SCEs) and cell division delays. A correlation between potency for SCE induction, effectiveness in cell division delay and previously established antitumor activity of these compounds was observed.

Antineoplastic Agents↗
PubMed1988

High-performance liquid chromatographic determination of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide, a 4-azasteroid, in human plasma from a phase I study.

A sensitive and selective high-performance liquid chromatographic method has been developed for the quantitative determination of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) in human plasma. I, a 5 alpha-reductase inhibitor and a potential therapeutic agent for benign prostatic hyperplasia, is a member of the family of compounds referred to as the 4-azasteroids. The 4-N-methyl analogue of the drug was used as the internal standard and calibration curves were developed at two levels of sensitivity to cover a large dynamic range of plasma concentrations. Drug was isolated from biological fluids with a solid-phase C18 extraction column; the analyte was further purified by adsorption and desorption from a second extraction column (CN cartridge). Evaluation of the isolation method revealed that it was reproducible and drug recoveries equalled ca. 90%. Chromatography was carried out on a C8 column (5 micron) with ultraviolet detection at 210 nm. The detection limit was ca. 10 ng/ml for I. Human plasma levels are reported for I following single-dose oral administration of 50,200 and 400 mg of drug; urinary excretion data are reported for a single volunteer given 400 mg of I.

5-alpha Reductase Inhibitors↗
PubMed2002

Synthesis of 17beta-N-substituted 19-Nor-10-azasteroids as inhibitors of human 5alpha-reductases I and II.

The synthesis of 17beta-[N-(phenyl)methyl/phenyl-amido] substituted 10-azasteroids has been accomplished by either the TiCl4- or TMSOTf-catalysed reaction of carbamates 11 and 12 with Danishefsky's diene. The reaction provided 5alpha-H isomers 3a-5a and 5beta-H isomers 3b-5b depending on the reaction conditions. Both epimers of each compound were tested against human 5alpha-reductase types I and II. Unexpectedly, 5beta-H compounds were found more active than their 5alpha-H counterparts, the best inhibitors being 3b (IC50=279 and 2000 nM toward isoenzyme I and II, respectively) and 5b (IC50=913 and 247 nM toward isoenzymes I and II, respectively).

5-alpha Reductase Inhibitors↗
PubMed2001

Mass spectral fragmentation reactions of a therapeutic 4-azasteroid and related compounds.

Mass spectra were acquired for a therapeutic 4-azasteroid (dutasteride), and some related compounds, using various ionization conditions (EI, CI, APCI and ESI) in both positive and negative ion modes. The ionization and fragmentation behavior of the compound dutasteride, its precursors and several analogs is reported. Positive atmospheric pressure chemical ionization (APCI+) and positive electrospray ionization (ESI+) produced distinctive collision-induced dissociation (CID) spectra for the respective [MH]+ ions of dutasteride. The spectral differences are attributed to ion populations having either different structures or different internal energy distributions (as a consequence of the method of ionization). Irrespective of their origin, the protonated molecules undergo interesting fragmentation reactions when collisionally activated. The identity of the major fragmentation products was confirmed by accurate mass measurement. The negative APCI mass spectrum of dutasteride displays extensive dehydrohalogenation, apparently due to the thermal component of the APCI process. Some of the resulting radical anions display remarkable stability toward collisional decomposition. Details of the fragmentation behavior for the negative ion species and their relationship to the positive ion results are discussed.

5-alpha Reductase Inhibitors↗
PubMed1995

Mechanism of time-dependent inhibition of 5 alpha-reductases by delta 1-4-azasteroids: toward perfection of rates of time-dependent inhibition by using ligand-binding energies.

Finasteride (17 beta-N-tert-butylcarbamoyl-4-aza-5 alpha-androstan-1-en-3- one) is a time-dependent, apparently irreversible inhibitor of 5 alpha-reductases, but does not fully inhibit the activity of 5 alpha-reductase in vivo. This limited efficacy has been attributed to its slow rate of inhibition against the type-1 isozyme [Tian, G. (1995) J. Pharm. Sci. (in press)]. Here the feasibility of increasing the rate of inhibition of 5 alpha-reductases by providing binding energies with the inhibitor at a site remote from the center of chemical transformation was explored. Substitution of N-(2,5-bis(trifluoromethyl)phenyl) group, which had been shown to benefit 6-azasteroids in the binding to 5 alpha-reductases [Frye, S., Haffner, C. D., Maloney, P. R., Hiner, R. N., Unwalla, R. J., Batchelor, K. W., Bramson, H. N., Stuart, J. D., Schweiker, S. L., Van Arnold, J., Bickett, D. M., Moss, M. L., Tian, G., Lee, F. W., Tippin, T. K., James, M. K., Grizzle, M. K., Long, J. E., & Croom, D. K. (1995) J. Med. Chem. 38, 2621-2627], for the N-tert-butyl substituent at C-17 of finasteride did not perturb the mechanism of inhibition but significantly increased the rate of inhibition of type-1 5 alpha-reductase. The rate of inhibition was too fast to determine accurately when the normal substrate testosterone was used in the progress curve analysis as this inhibition rate is approaching the value of kcat/Km for the enzyme reaction.

5-alpha Reductase Inhibitors↗
PubMedDate not supplied

QSARs for 6-azasteroids as inhibitors of human type 1 5alpha-reductase: prediction of binding affinity and selectivity relative to 3-BHSD.

Quantitative structure-activity relationships (QSARs) are developed to describe the ability of 6-azasteroids to inhibit human type 1 5alpha-reductase. Models are generated using a set of 93 compounds with known binding affinities (K(i)) to 5alpha-reductase and 3beta-hydroxy-Delta(5)-steroid dehydrogenase/3-keto-Delta(5)-steroid isomerase (3-BHSD). QSARs are generated to predict K(i) values for inhibitors of 5alpha-reductase and to predict selectivity (S(i)) of compound binding to 3-BHSD relative to 5alpha-reductase. Log(K(i)) values range from -0.70 log units to 4.69 log units, and log(S(i)) values range from -3.00 log units to 3.84 log units. Topological, geometric, electronic, and polar surface descriptors are used to encode molecular structure. Information-rich subsets of descriptors are identified using evolutionary optimization procedures. Predictive models are generated using linear regression, computational neural networks (CNNs), principal components regression, and partial least squares. Compounds in an external prediction set are used for model validation. A 10-3-1 CNN is developed for prediction of binding affinity to 5alpha-reductase that produces root-mean-square error (RMSE) of 0.293 log units (R(2) = 0.97) for compounds in the external prediction set. Additionally, an 8-3-1 CNN is generated for prediction of inhibitor selectivity that produces RMSE = 0.513 log units (R(2) = 0.89) for the external prediction set. Models are further validated through Monte Carlo experiments in which models are generated after dependent variable values have been scrambled.

Azasteroids↗
PubMed1981

The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments.

Nine analogues of the azasteroid muscle relaxant chandonium have been tested for neuromuscular blocking activity, ganglion blocking activity, inhibitory effects on cardiac muscarinic receptors, and for effects on noradrenergic transmission. Experiments were performed in anaesthetized cats and in isolated preparations. The two bisquaternary compounds HS-626 and HS-627, choline and acetylcholine-like analogues of chandonium respectively, were approximately equipotent with chandonium as neuromuscular blocking agents in the cat, but HS-672 possessed slightly more vagal blocking action. No evidence was obtained for ganglion block. The monoquaternary analogues, HS-408 and HS-465 and two 4-aza-androstanes, (HS-522 and HS-523) were more than 100 times less active than the bisquaternary compounds as neuromuscular blocking agents, and produced vagal blockade and ganglion blockade at sub-neuromuscular blocking doses. pA2 determinations in the chick biventer cervicis muscle, the guinea-pig atria and guinea-pig ileum showed that the bisquaternary compounds chandonium, HS-626 and HS-627 were much more potent in blocking cardiac than intestinal muscarinic receptors and that HS-626 possessed the widest margin between concentrations blocking the nicotinic receptors at the neuromuscular junction and the cardiac muscarinic receptors. Evidence for the three bisquaternary compounds blocking neuronal noradrenaline reuptake was obtained only at very high concentrations. HS-626 possessed a slightly more desirable spectrum of activities than chandonium, but the degree of improvement over the parent compound is insufficient to merit extensive clinical testing.

Acetylcholine↗
PubMedDate not supplied

[Immunomodulators with an 8-azasteroid structure as inducers of liver cytochrome P-450].

Two structural analogues of D-homo-8-azasteroids, both an immunostimulant and an immunodepressant, are inductors of the liver cytochrome P-450 in animals. This capability was shown by means of both a decrease of the hexenal sleep duration in the pharmacological test and an increase of the quantity of cytochrome P-450 and the rate of N-demethylation of aminopyrine in the biochemical assays.

Adjuvants, Immunologic↗
PubMed1996

Synthesis of an Azasteroid Using an Acyl Iminium Ion-Initiated Tandem Cyclization.

An acyl iminium ion-initiated tandem cyclization gave an unexpected dienone product, a seco-azasteroid (2). The factors governing the formation of 2 were investigated in an attempt to optimize its formation. The reaction was applied to a more elaborate system, resulting in the synthesis of the full steroid skeleton of 13-azaandrosta-1,4-diene-3,17-dione (3), which contains the unusual substitution of a chlorine atom for the axial 19-methyl.

Journal Article↗
PubMed1996

Photoaffinity labeling of rat steroid 5 alpha-reductase (isozyme-1) by a benzophenone derivative of a 4-methyl-4-azasteroid.

[1,2-3H]N-4(Benzylbenzoyl)-3-oxo-4-aza-4-methyl-5 alpha-androstane-17 beta-carboxamide ([3H]-4MABP) has been synthesized as a photoaffinity probe of the steroid-binding domain of rat steroid 5 alpha-reductase isozyme-1 (5 alpha R-1). Reversible binding of the probe to 5 alpha R-1 in microsomal preparations yielded a reversible dissociation constant (Kd) of -3 nM, whereas inhibition experiments indicated that the probe had a 50% inhibition concentration of 4.4 nM and was a competitive inhibitor of the enzyme (Ki approximately 3 nM) with respect to testosterone. SDS-PAGE analysis of microsomal, detergent-solubilized, and (6.5%) polyethylene glycol-precipitated fractions of 5 alpha R-I photolyzed with [3H]4MABP in the presence of NADPH showed that the radioactivity was incorporated into a single protein band with a mass of 26 kDa (apparent molecular weight of 5 alpha R-1). UV photolysis was accompanied by an irreversible loss in enzyme activity, consistent with its covalent modification. Increasing the time of UV irradiation and concentration of [3H]4MABP indicated that the half-life and apparent Kd for its photo insertion were approximately 3 min and 7.5 nM, respectively. Photolysis in the presence of a 20-fold excess of N,N-diethyl-4-aza-4-methyl-3-oxo-5 alpha-androstane-17 beta-carboxamide or the 3-carboxysteroid SKF-105111 resulted in partial protection of 5 alpha R-1 from the probe, whereas minimal incorporation of radioactivity was observed in the absence of NADPH or in the presence of NADP+. The results indicate that [3H]4MABP is an effective probe of the steroid (D-ring) binding domain of 5 alpha R-1.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1986

Mutagenicity and clastogenicity of the antineoplastic agents homo-azasteroidal ester of p-bis(2-chloroethyl)aminophenyl acetic acid and chlorambucil.

The mutagenic and clastogenic effects of the antineoplastic agents homo-aza-steroidal ester (ASE) and chlorambucil (CBC) were tested for their ability to induce mutations in the Salmonella/microsome system and SCE in CHO cells in culture. ASE was found to be positive in strains TA1535 and TA100 and in the newer strain TA102 with and without metabolic activation, while CBC caused histidine reversion in strain TA102 after the addition of mammalian liver microsomal extract (S9). In addition, both agents were found to be strongly positive for SCE induction. The mutagenic and clastogenic actions of both agents were of a dose-response type.

Animals↗
PubMed1992

Kinetic mechanism of reduction of testosterone by hepatic 5 beta-reductase of chicken and inhibition of the reductase activity by a secosteroid, an azasteroid and glycyrrhetinic acid.

The present studies on initial velocity of testosterone reduction by hepatic 5 beta-reductase (4-en-3-oxosteroid 5 beta-reductase) of chicken and mode of inhibition of the 5 beta-reduction by 5 beta-dihydrotestosterone and NADP+ indicated that the reduction of testosterone occurred after the 5 beta-reductase bound firstly to NADPH and then to testosterone, forming a ternary complex. After 5 beta-reduction, 5 beta-dihydrotestosterone and then NADP+ were liberated from the complex, following a mechanism of "ordered Bi-Bi". Effect of (4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-trione (a steroidal 5 alpha-reductase-inhibitor or Secosteroid), diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (the other steroidal 5 alpha-reductase-inhibitor or 4-MA), and glycyrrhetinic acid (3 beta-hydroxy-11-oxoolean-12-en-30-oic acid, a 5 beta-reductase-inhibitor) was examined upon the 5 beta-reductase activity by double reciprocal plots. The mode of inhibition against testosterone by 4-MA and glycyrrhetinic acid was found to be competitive, while that by Secosteroid was non-competitive.

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

Synthesis and study of some 4-aza and 17a-azasteroidal isoxazoles.

4-Aza-5 alpha-androstano[2,3-d]isoxazole 4 and 17a-aza-D-homo-5-androsteno[17,16-c]isoxazole 7 have been prepared by treating alpha,beta-unsaturated-beta-chloroaldehydes 3 and 6 [1, 2] with hydroxylamine hydrochloride in pyridine. [16,17-d]Isoxazole derivatives 4 and 8 were found to be unstable in most of the organic solvents. beta-Cyanolactam derivatives 5 and 9 have also been prepared in both the series.

Androstenes↗
PubMed1997

Low level determination of a novel 4-azasteroid and its carboxylic acid metabolite in human plasma and semen using high-performance liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

Compound I (4.7beta-dimethyl-4-azacholestan-3-one, MK-0386) is a potent 5alpha-reductase type 1 (5alphaR1) inhibitor. Sensitive (0.2 ng/ml), specific and separate assays have been developed and validated for the analysis of I and its carboxylic acid metabolite (II) in human semen and plasma based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. After liquid-liquid extraction of the analytes from biological matrix, the extracts were chromatographed on a short (50 mm) analytical column during analysis of I, and on a longer (150 mm) column with a weaker mobile phase during the analysis of II. This additional chromatographic separation was required to separate II from a secondary metabolite present in post-dose plasma samples interfering with the quantification of II. The MS-MS detection was performed on a Sciex API III Plus tandem mass spectrometer using the heated nebulizer probe. Monitoring the parent-->product ion combinations of m/z 416-->114 and 404-->114, in the multiple reaction monitoring (MRM) mode, after chromatographic separation, allowed quantification of both analytes. The standard curve in plasma was linear in the concentration range of 0.2 to 200 ng/ml for both I and II with correlation coefficients greater than 0.99 and coefficients of variation of less than 15% for replicate (n=5) analysis at all concentrations within the standard curve range. For the semen assay the linear range for determination of I was from 0.2 to 50 ng/ml. These assays were applied to support a number of clinical studies with I and their validity and long-term performance was confirmed during analyses of clinical samples from these studies. The need for careful assessment of the specificity of MS-MS assays in post-dose biological fluid samples in the presence of metabolites was emphasized.

5-alpha Reductase Inhibitors↗