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| | Dutasteride Basic information |
| Product Name: | Dutasteride | | Synonyms: | (1S,2R,7R,10S,11S,14S,15S)-N-[2,5-bis(trifluoroMethyl)phenyl]-2,15-diMethyl-5-oxo-6-azatetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadec-3-ene-14-carboxaMide;(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-[2,5-Bis(trifluoroMethyl)phenyl]-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-4a,6a-diMethyl-2-oxo-1H-Indeno[5,4-f]quinoline-7-carboxaMide;(5α,17β)-;(4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-[2,5-Bis(trifluoroMethyl)phenyl]-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-4a,6a-diMethyl-2-oxo-1H-indeno[5,4-f]quinoline-7-carboxaMide-13C6;6β-Hydroxy Dutasteride;4-Azaandrost-1-ene-17-carboxaMide, N-[2,5-bis(trifluoroMethyl)phenyl]-3-oxo-, (5a,17b)-;Avolve;5,6-Dehydro-17α | | CAS: | 164656-23-9 | | MF: | C27H30F6N2O2 | | MW: | 528.53 | | EINECS: | 638-758-5 | | Product Categories: | Hormone Drugs;API;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Steroids;Miscellaneous Biochemicals;All Inhibitors;Steroid and Hormone;164656-23-9 | | Mol File: | 164656-23-9.mol |  |
| | Dutasteride Chemical Properties |
| Melting point | 242-250°C | | Boiling point | 620.3±55.0 °C(Predicted) | | density | 1.303±0.06 g/cm3(Predicted) | | storage temp. | -20°C | | solubility | DMSO: soluble2mg/mL, clear | | form | powder | | pka | 13.32±0.70(Predicted) | | color | white to beige | | optical activity | [α]/D +18 to +24°, c = 1 in chloroform-d | | BCS Class | 2/4 | | InChIKey | JWJOTENAMICLJG-QWBYCMEYSA-N |
| | Dutasteride Usage And Synthesis |
| Description | Dutasteride is a synthetic 4-azasteroid compound. It is a dual inhibitor of type 1 and 2 isoforms of 5α-reductase unlike finasteride, the first marketed 5α-reductase inhibitor, which only acts on type 2 isozyme. Dutasteride is a 3-fold greater inhibitor of type-2 5α-reductase than finasteride in men and has greater effect on the type-l than on type-2 isozyme. In animal models,dutasteride exhibited superior efficacy and pharmacokinetics compared to finasteride. In patients with benign prostate hyperplasia, administration of dutasteride was shown to dose-dependently decrease serum dihydrotestosterone levels with greater efficacy as compared to finasteride (95% vs 67%). Serum testosterone levels increased with both active drugs, in conjunction with dihydrotestosterone suppression but remained within normal ranges. In long term studies, in men with moderate to severe benign prostate hyperplasia, once daily dutasteride significantly reduced prostate volume, reduced the risk of acute urinary retention and surgery by 57% and improved lower urinary tract symptoms and urinary flow measurements. | | Chemical Properties | Dutasteride is a white to pale yellow powder It is soluble in ethanol (44 mg/mL), methanol (64 mg/mL), and polyethylene glycol 400 (3 mg/mL), but it is insoluble in water. | | Originator | GlaxoSmithKline (UK) | | Uses | Dutasteride is a dual inhibitor of 5a-reductase isoenzymes type 1 and 2; structurally related to Finasteride. Dutasteride is used in the treatment of benign prostatic hyperplasia. Dutasteride is associated with a low rate of transient serum aminotransferase elevations, but has yet to be linked to instances of clinically apparent acute liver injury. | | Definition | ChEBI: Dutasteride is an aza-steroid that is inasteride in which the tert-butyl group is replaced by a 2,5-bis(trifluoromethyl)phenyl group. A synthetic 4-azasteroid, dutasteride is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5alpha-reductase, an intracellular enzyme that converts testosterone to 5alpha-dihydrotestosterone. Dutasteride is used for the treatment of symptomatic benign prostatic hyperplasia in men with an enlarged prostate gland. It has a role as an EC 1.3.1.22 [3-oxo-5alpha-steroid 4-dehydrogenase (NADP(+))] inhibitor and an antihyperplasia drug. It is an aza-steroid, a member of (trifluoromethyl)benzenes and a delta-lactam. It derives from a hydride of a 5alpha-androstane. | | Brand name | Avodart (GlaxoSmithKline). | | Biological Functions | Similar to finasteride, dutasteride is a competitive and mechanism-based inhibitor not only of type 2
but also of type 1 5α-reductase isoenzymes, with which stable enzyme-NADP adduct complexes are
formed, inhibiting the conversion of testosterone to DHT. The suppression of both type 1 and
type 2 isoforms results in greater and more consistent reduction of plasma DHT than that observed
for finasteride. The more effective dual inhibition of type 1 and type 2 5α-reductase
isoforms lowers circulating DHT to a greater extent than with finasteride and shows advantages in
treating BPH and other disease states (e.g., prostate cancer) that are DHT-dependent. | | Biochem/physiol Actions | Dutasteride is a potent dual inhibitor of 5α-reductase isoenzymes types 1 and 2 (IC50 = 6 nM 5-AR1; 7 nM 5-AR2). Dutasteride blocks testosterone conversion to dihydrotesterone, and is used clinically for treating benign prostatic hyperplasia (BPH). | | Pharmacokinetics | The maximum effect of 0.5 mg daily doses of dutasteride on the suppression of DHT is
dose-dependent and is observed within 1 to 2 weeks. After 2 weeks of 0.5 mg daily dosing, median
plasma DHT concentrations were reduced by 90%, and after 1 year, the median decrease in plasma
DHT was 94%. The median increase in plasma testosterone was 19% but remained within
the physiological range. The drug also reduced serum prostatic specific antigen by approximately
50% at 6 months and total prostate volume by 25% at 2 years. Dutasteride produced improvements in
quality of life and peak urinary flow rate and reduction of acute urinary retention without the need for
surgery. | | Clinical Use | Dutasteride belongs to azasteriod class of compounds and function as a 5α-reductase inhibitor1 which prevents the conversion of the androgen sex hormone testosterone into the more potent metabolite dihydrotestosterone (DHT). In 2009, South Korea has been licensed dutasteride for the treatment of androgenetic alopecia and in Japan 2015.
Dutasteride is the first and only double 5α reductase inhibitor used to treat Benign prostatic hyperplasia, and it is mainly used clinically to treat prostate enlargement, male-pattern hair loss, seborrheic hair loss, and hereditary hair loss. | | Side effects | The main side effects are ED, decreased libido, gynecomastia, and ejaculation disorders.
Long-term use (>4 years), however, did not reveal increased onset of sexual side effects. In addition,
the combination of dutasteride and tamsulosin is well-tolerated and has the added advantage of rapid
symptomatic relief. | | Synthesis | Dutasteride can be prepared from 3-oxo-4-androstene-17β-carboxylic acid by several ways in 6 or 8 steps. In the preparation of dutasteride, the introduction of the carbon-carbon double bond in conjugation with C-3 carbonyl carbon of azaandrosteriods is one of the most important chemical reaction.
an efficient synthesis of dutasteride: utilizing benzoyl group as novel lactamic protecting group | | in vivo | dutasteride, which inhibits both 5αr1/5αr2, is efficacious in blocking prostate cancer development or progression in c57bl/6 tramp x fvb mice [2]. | | Metabolism | Dutasteride is metabolised by the cytochrome P450
isoenzymes CYP3A4 and CYP3A5, and most of a dose is
excreted as metabolites in the faeces. | | Mode of action | The human body contains type I and type II 5α reductase, with type II found mainly in the prostate, and type I found mainly in the liver and skin. 5α reductase is the main cause for continuous benign prostate enlargement; it promotes the transformation of testosterone in patients’ prostate into the more active dihydrotestosterone, thus causing prostate cells to enlarge and the prostate to swell. Dutasteride can inhibit both type I and II 5α reductase at the same time. This type of simultaneous inhibiting mechanism can rapidly and continuously reduce prostate size, dramatically improve urination, and reduce the risk fo acute urinary retention and its related prostate surgeries. | | Clinical claims and research | The American FDA approved a 2-year multicenter randomized double-blind control clinical trial – the first long term clinical assessment of the combined usage of Dutasteride and α receptor blockers. Included subjects were male patients with moderate to severe prostate enlargement (ages greater than or equal to 50, prostate volume (PV) ≥30 cc, serum prostate specific antigen (PSA) levels 1.5-10ng/ml, 5ml/sec < maximum urinary flow (Qmax) ≤15ml/sec, minimum urination ≥ 125ml, international prostate symptom score (IPSS) ≥ 12). Patients were first given a placebo for 4 weeks and then were randomly given either 0.5mg/day of Dutasteride and 0.4mg/day of Tamsulosin, only 0.5mg/day of Dutasteride, or only 0.4mg/day of Tamsulosin.
Results showed: After 12-24 months, the combined usage of Dutasteride with Tamsulosin had better curative effects than did individual usage. | | references | [1] schmidt lj1, murillo h, tindall dj. gene expression in prostate cancer cells treated with the dual 5 alpha-reductase inhibitor dutasteride. j androl. 2004 nov-dec;25(6):944-53.
[2] opoku-acheampong ab1, unis d, henningson jn, beck ap, lindshield bl.preventive and therapeutic efficacy of finasteride and dutasteride in tramp mice. plos one. 2013 oct 18;8(10):e77738. doi: 10.1371/journal.pone.0077738. ecollection 2013. |
| | Dutasteride Preparation Products And Raw materials |
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