Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of 17 beta-acylurea-4-aza-5 alpha-androstan-3-one derivatives has been assayed in vitro as inhibitors of testosterone 5 alpha-reductase, using the particulate fraction of human hyperplastic prostate and rat prostate as enzyme sources. The most active derivatives were 1-[4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carbonyl]- 1,3-dicyclohexylurea (compound 1) and 1-[4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carbonyl]- 1,3-diisopropylurea (compound 3) which demonstrated IC50 values of 41 and 55 nM for the human enzyme and of 83 and 53 nM for the rat enzyme, respectively. Neither compound showed any relevant binding affinity to the rat prostate androgen receptor (IC50 of approximately 100 and 84 microM). When given orally in immature castrated rats together with subcutaneous testosterone propionate (TP) for 7 consecutive days, compound 3 (laboratory code FCE 26073), at 3 mg/kg/day, significantly decreased the ventral prostate growth promoting effect of TP by 40-50%, whereas compound 1 was ineffective up to the dose of 10 mg/kg/day.
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PMID:17 beta-acylurea derivatives of 4-azasteroids as inhibitors of testosterone 5 alpha-reductase. 137 5

Exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione) is a novel orally active irreversible aromatase inhibitor. Its in vitro and in vivo pharmacological properties have been compared to 4-hydroxyandrostenedione (4-OHA). In preincubation studies with human placental aromatase, exemestane, like 4-OHA, showed enzyme inactivating properties with a similar affinity (Ki 26 vs 29 nM) and a lower rate of inactivation (t1/2 13.9 vs 2.1 min). Conversely, when tested in pregnant mares' serum gonadotropin-treated rats, exemestane was more potent in reducing microsomal ovarian aromatase activity than 4-OHA, after both subcutaneous (ED50 1.8 vs 3.1 mg/kg) and oral dosing (ED50 3.7 vs greater than 100 mg/kg). No interference of exemestane on desmolase or 5 alpha-reductase activity was found. The compound did not show any relevant binding affinity to steroidal receptors, but slight binding to the androgen receptor (approximately 0.2% of dihydrotestosterone), like 4-OHA. In the first phase I trial, healthy postmenopausal volunteers were given single oral doses of exemestane, ranging from 0.5 to 800 mg, and plasma [estrone (E1), estradiol (E2) and estrone sulphate (E1S)] and urinary estrogens (E1 and E2) were measured up to 5-8 days. The minimal effective dose in decreasing estrogens was 5 mg. At 25 mg the maximal suppression was observed at day 3: plasma estrogens fell to 35 (E1), 39 (E2) and 28% (E1S), and urinary estrogens fell to 20 (E1) and 25% (E2) of basal values, these effects still persisting on day 5. No effects on plasma levels of cortisol, aldosterone, 17-hydroxyprogesterone, DHEAS, LH and FSH, and no significant adverse events were observed up to the highest tested dose of 800 mg exemestane.
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PMID:Exemestane (FCE 24304), a new steroidal aromatase inhibitor. 152 55

FCE 24928 (4-aminoandrosta-1,4,6-triene-3,17-dione) was selected among a series of 4-aminoandrostenedione derivatives as a novel irreversible aromatase inhibitor. Its in vitro and in vivo properties have been studied and compared to FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione) and 4-OHA (4-hydroxyandrostenedione). FCE 24928 caused time-dependent inhibition of human placental aromatase with a t1/2 of 4 min and Ki of 59 nM. Enzyme inactivation by FCE 24928 was faster than by FCE 24304 (t1/2 13.9 min). In PMSG-treated rats, microsomal ovarian aromatase activity was reduced 24 h after FCE 24928 dosing by both the s.c. (ED50 1.2 mg/kg) and the oral (ED50 14.1 mg/kg) routes. The compound was more potent than FCE 24304 and 4-OHA (ED50 1.8 and 3.1 mg/kg s.c.). FCE 24928 did not show any interference with 5 alpha-reductase and desmolase activity nor any significant binding affinity for androgen and estrogen receptors. Slight binding affinity for androgen receptor was observed with FCE 24304 and 4-OHA (0.21 and 0.25% of DHT). In immature, castrated rats, FCE 24928 did not show any intrinsic androgenic activity, up to 100 mg/kg/day s.c., in contrast to a slight androgenic activity observed with FCE 24304 at 10 mg/kg s.c.
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PMID:4-Aminoandrostenedione derivatives: a novel class of irreversible aromatase inhibitors. Comparison with FCE 24304 and 4-hydroxyandrostenedione. 225 40

FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione), a new irreversible aromatase inhibitor, has been identified and characterized in vitro and in vivo. The compound caused time-dependent inactivation of human placental aromatase with a t1/2 of 13.9 min and ki of 26 nM. When tested in PMSG-treated rats, ovarian aromatase activity was reduced 24 h after dosing by both the s.c. (ED50 1.8 mg/kg) and the oral (ED50 3.7 mg/kg) routes. No interference with 5 alpha-reductase activity nor any significant binding affinity for estrogen receptor was found. Slight binding affinity for the androgen receptor (RBA 0.2% of DHT) was observed.
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PMID:6-Methylenandrosta-1,4-diene-3,17-dione (FCE 24304): a new irreversible aromatase inhibitor. 338 66

FCE 27837 is a novel inhibitor of 5 alpha-reductase, the enzyme responsible for the conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). The compound caused inhibition of human and rat prostatic enzymes, with IC50 values of 51 and 60 nM, respectively. The in vivo effect of FCE 27837 on 5 alpha-reductase was evaluated in adult male rats, treated orally at 10 mg/kg/day for 10 days. The compound caused 33 and 42% reductions in ventral prostate and seminal vesicle weights, respectively. The prostatic content of DHT, measured 6 h after the 10th dose of FCE 27837, was reduced by 75%, whereas T content increased by 442%. Similar effects were observed with 10 mg/kg/day of finasteride, whereas epristeride, tested at the same oral dose, was found to be the least effective compound, decreasing prostate weight by 22% and DHT content by 46%. Castration caused > 90% reductions in prostatic weight and prostatic DHT.
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PMID:Effects of 5 alpha-reductase inhibitors on intraprostatic androgens in the rat. 762 85

An antiserum against turosteride (code name FCE 26073), a potent testosterone 5 alpha-reductase inhibitor, has been raised in rabbits by immunization with an immunogen produced by conjugation of a derivative of FCE 26073 (FCE 27424) to bovine serum albumin. The antiserum was able to distinguish FCE 26073 from its derivatives modified at the 17 beta position and from all the endogenous steroids tested. A radioimmunoassay for the determination of FCE 26073 in human plasma and urine was developed using this antiserum and tritium labeled turosteride. FCE 26073 was extracted from 50 microliters of plasma or 25 microliters of urine using ethyl-ether with a recovery greater than 90%. Using this procedure it was possible to achieve a final limit of quantitation of 142 pg/ml in plasma and 284 pg/ml in urine. The assay was validated in terms of reproducibility, accuracy and precision in the range 3.9-250 pg/50 microliters of plasma and 25 microliters of urine. The plasma concentration of FCE 26073 in a healthy male volunteer who received 0.2 mg of the drug was measured using the radioimmunoassay.
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PMID:Radioimmunoassay for the testosterone 5 alpha-reductase inhibitor turosteride in biological fluids. 804 Mar 53

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.
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PMID:Novel aromatase and 5 alpha-reductase inhibitors. 804 91

Turosteride [FCE 26073; 1-(4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carbonyl)-1,3- diisopropylurea] is a novel inhibitor of 5 alpha-reductase, the enzyme responsible for the conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 55 and 53 nM, respectively. In addition, turosteride did not show any relevant binding affinity to the rat prostate androgen receptor (IC50 84 microM; relative binding affinity 0.004% of DHT). The endocrine effects of turosteride were evaluated in adult male rats, treated orally at daily doses of 3, 10 and 30 mg/kg for 20 days. At these doses, the compound reduced the ventral prostate weight by 10, 33 and 42% and the intraprostatic total DHT content by 61, 74 and 78%, respectively, whereas no change in the intraprostatic content of T was observed. Turosteride caused a 40% reduction of serum DHT levels which, however, did not reach statistical significance, whereas serum T levels were similar to control animals. No effect on serum luteinizing hormone or prolactin was observed. These results indicate that the antiprostatic effect of turosteride in the adult rat is related to inhibition of the conversion of T to DHT. However, at variance with other 5 alpha-reductase inhibitors (e.g. finasteride), turosteride caused a decrease in prostatic DHT not associated with a secondary increase in T content. This peculiarity of turosteride may represent an improvement of the compound over other inhibitors.
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PMID:Hormonal effects of turosteride, a 5 alpha-reductase inhibitor, in the rat. 824 Sep 76

FCE 28260 is a novel inhibitor of 5 alpha-reductase (5 alpha R), the enzyme responsible for the conversion of testosterone (T) to 5 alpha-dihydrotestosterone (DHT). The compound caused inhibition of rat and human prostatic enzymes, with IC50 values of 15 and 16 nM, respectively, compared to the values of 30 and 52 nM shown by finasteride. Furthermore, FCE 28260 was highly potent in inhibiting human recombinant 5 alpha R type 2 and 1 isozymes, showing IC50 values of 3.3 and 36 nM, and therefore it was more potent than finasteride (IC50 values of 8.5 and 470 nM) on both isozymes. In prepubertal, T-implanted castrated rats, FCE 28260, given orally for 7 days, reduced ventral prostate growth with an ED50 of 0.8 mg/kg, i.e. five times lower than that shown by finasteride. No anti-androgenic activity in DHT-implanted castrated rats was found up to 10 mg/kg/day. In adult male rats, FCE 28260 reduced prostatic DHT concentrations 6 h after oral dosing with a potency similar to that of finasteride (65% reduction at 1 mg/kg) but was found to be markedly more potent than the reference compound at 24 h (74% reduction in prostate DHT at 10 mg/kg, compared to 26% reduction induced by finasteride). These results indicate that FCE 28260 represents a marked improvement over finasteride.
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PMID:FCE 28260, a new 5 alpha-reductase inhibitor: in vitro and in vivo effects. 883 65

The efficacy of treatment with the 5 alpha-reductase inhibitor PNU 156765 (FCE 28260) was investigated in the Dunning R3327 prostatic tumor in rats. The compound, given orally at the doses of 10 and 50 mg/kg/day, for 8 weeks, reduced the growth of established tumors by 49-50%, an effect similar to that of flutamide at 5 mg/kg/day (46% inhibition). In a further experiment, the combination of PNU 156765 10 mg/kg/day and flutamide 5 mg/kg/day resulted in greater inhibition than either treatment alone (70 vs. 20% in PNU-156765-treated and 51% in flutamide-treated groups). The effect of the combination was similar to that of castration (75% inhibition). Ventral prostate weight was more markedly reduced by PNU 156765 than by flutamide, and combined treatment was as effective as castration. Prostatic dihydrotestosterone content was markedly reduced by PNU 156765 while prostatic testosterone increased. Concomitant treatment with flutamide antagonized the testosterone increase induced by PNU 156765. These data indicate a role for 5 alpha-reductase inhibitors in the therapy of prostate cancer, in combination with antiandrogens, in order to achieve adequate androgen blockade with minimal side effects.
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PMID:Effect of the 5 alpha-reductase inhibitor PNU 156765, alone or in combination with flutamide, in the Dunning R3327 prostatic carcinoma model in rats. 968 Dec 5


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