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At least 55 records · Page 3Linked to original sources
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↗
PubMed1994

6-Azasteroids: structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase.

6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.

3-Hydroxysteroid Dehydrogenases↗
PubMed1977

Synthesis and antimicrobial activity of azasteroid-type compounds and related systems. Effect of hydrophilic and lipophilic groups on activity.

Pyrazole-, pyrazolone- and isoxazole-containing systems were prepared from 3,4-dihydro-6-(hexyloxy)-1(2H)-naphthalenone, 3,4-dihydro-6-(hexadecyloxy)-1(2H)-naphthalenone,3,4-dihydro-6(2-dimethylaminoethyloxy)-1-(2H)-naphthalenone, 3,4-dihydro-7-hexyloxy-1(2H)-phenanthrone, and 3,4-dihydro-7-(2-dimethylaminoethyloxy)-1(2H)-phenanthrone. A number of compounds derived from 7, 8-dihydro-5(6H)-quinolinone were also synthesized and characterized. Both hydrophilic and lipophilic groups were incorporated into certain systems as well as cidal groups. The compounds were screened for their in vitro inhibitory activity against Bacillus subtilis and Pseudomonas fluorescens. Structure-acitivity relationships among the molecular systems are discussed.

Anti-Bacterial Agents↗
PubMed2003

Two azasteroidal [3,2-c]pyrazole derivatives: 2'-(p-fluorophenyl)-4-azapyrazolo[4',3':2,3]-5alpha-androstan-17beta-yl acetate and 2'-(p-fluorophenyl)-4-azapyrazolo[4',3':2,3]-5alpha-androstan-17beta-ol.

In both the title aza-steroids, 2'-(p-fluorophenyl)-4-azapyrazolo[4',3':2,3]-5alpha-androstan-17beta-yl acetate, C(27)H(34)FN(3)O(2), (I), and 2'-(p-fluorophenyl)-4-azapyrazolo[4',3':2,3]-5alpha-androstan-17beta-ol, C(25)H(32)FN(3)O, (II), the tetrahydropyridine ring adopts a half-chair conformation and is considerably strained as a consequence of the presence of the fused planar pyrazole ring. In both compounds, both cyclohexane rings have chair conformations, while the cyclopentane ring has an envelope conformation. All the rings of the steroid nucleus are trans fused. In (I), intermolecular N-H.O, C-H.F, C-H.O and C-H.N interactions are observed in the solid state, while intermolecular N-H.O and O-H.N hydrogen bonds are observed in (II).

Acetates↗
PubMed1979

Mode of action of the azasteroid antibiotic 15-aza-24 methylene-d-homocholesta-8,14-dien-3 beta-ol in Ustilago maydis.

Ustilago maydis sporidia treated with 0.1 mug of azasterol (15-aza-24-methylene-d-homocholesta-8,14-dien-3beta-ol) per ml appeared branched and vacuolated after 6 h of incubation. Sporidial multiplication, dry weight increase, and synthesis of protein, deoxyribonucleic acid, and ribonucleic acid were only slightly or moderately inhibited during the initial 3 h of incubation. An increase of free fatty acids was observed in lipid extracts of treated sporidia after incubation for 3 h or more. Ergosterol synthesis was completely inhibited within 1 h and there was a gradual decline of ergosterol content during 6 h which was accompanied by an accumulation of the sterol intermediate ergosta-8,14-dien-3beta-ol. The results indicate that toxicity of the azasterol results from specific inhibition of the reduction of the sterol C-14(15) double bond. A triarimol-tolerant strain of Cladosporium cucumerinum was tolerant to the azasterol, but an imazalil-tolerant strain of Aspergillus nidulans was not.

Antifungal Agents↗
PubMedDate not supplied

[11-azasteroids. V. Hormonal properties of 11-azaestranes].

Experiments were conducted on sexually-immature female rats, ovariectomized mice and castrated male rats. Hormonal properties of some 11-azaestran were studied. As shown, introduction of azafunction into the position of the 11 molecule of the steroid sharply reduced the hormonal activity, irrespective of other functions in the molecule determining the reference of the steroid to the estron, estradiol, or 19-nortestosterone series.

Anabolic Agents↗
PubMed1984

Selective inhibition of prostatic tumor 5 alpha-reductase by a 4-methyl-4-azasteroid.

The effect of sodium 4-methyl-3-oxo-4-aza-5 alpha-pregnane-20(s)-carboxylate (4-MAPC) on testosterone metabolism was investigated in rat and human prostates in organ culture. The general properties of the test system for androgen metabolism and response to inhibitors were in close agreement with in vivo observations. As an inhibitor of prostatic tumor 5 alpha-reductase, 4-MAPC was equally as effective as 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one, reported to be a potent 5 alpha-reductase inhibitor. Inhibition of 5 alpha-reductase activity by 4-MAPC, but not by 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one, was accompanied by concomitant stimulation of 17 beta-oxidation of testosterone. This differential effect was observed in explants of human prostatic carcinoma and benign prostatic hypertrophy containing a relatively high degree of glandular hyperplasia. It was also seen in explants of dorsolateral rat prostate but not in the ventral prostate. 4-MAPC exhibited low affinity for rat prostatic cytosol 8S androgen receptor. Steroid extraction of purified nuclei from inhibited rat tissues revealed substantial amounts of radioactivity derived from [3H]testosterone cochromatographed with other metabolites in addition to dihydrotestosterone. The endocrine changes produced by this inhibitor of 5 alpha-reductase are reconcilable with the responsiveness of androgen-sensitive malignant prostatic cells to hormonal therapy.

5-alpha Reductase Inhibitors↗