164656-23-9 Usage
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].
Drug interactions
Potentially hazardous interactions with other drugsNone known
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.
Check Digit Verification of cas no
The CAS Registry Mumber 164656-23-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,6,4,6,5 and 6 respectively; the second part has 2 digits, 2 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 164656-23:
(8*1)+(7*6)+(6*4)+(5*6)+(4*5)+(3*6)+(2*2)+(1*3)=149
149 % 10 = 9
So 164656-23-9 is a valid CAS Registry Number.
InChI:InChI=1/C27H30F6N2O2/c1-24-11-9-17-15(4-8-21-25(17,2)12-10-22(36)35-21)16(24)6-7-19(24)23(37)34-20-13-14(26(28,29)30)3-5-18(20)27(31,32)33/h3,5,10,12-13,15-17,19,21H,4,6-9,11H2,1-2H3,(H,34,37)(H,35,36)/t15?,16?,17?,19-,21?,24+,25-/m1/s1
164656-23-9Relevant articles and documents
Production process of high-purity dutasteride
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Paragraph 0046; 0047; 0053-0055; 0058-0060; 0069-0077, (2018/04/02)
The invention discloses a purification production process of high-purity dutasteride. The problems to be solved are that the purity of the dutasteride is improved while the production cost is reduced.According to the method, after a dutasteride crude product is obtained, twice crystallization is carried out, so that the dutasteride with high yield and high purity can be obtained. The production process provided by the invention has the advantages of high efficiency and clean production, and the operability is high. An intermediate is refined, so that the quality of the dutasteride finished product is more easily controlled, the purity of the obtained dutasteride product is not lower than 99.5%, and any single impurity in the product is not higher than 0. 1%.
A androst - 17β - N - (2, 5 - (trifluoromethyl)-) IBZM preparation method
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Paragraph 0039; 0040; 0041; 0046; 0047, (2018/01/02)
The invention provides a preparation method of androstane-17beta-N-(2,5-bis (trifluoromethyl)) benzamide. The preparation method comprises the following steps: (1) in the presence of an acid-binding agent, carrying out acyl chloride forming reaction between androstane-17beta carboxylic acid and thionyl chloride to obtain androstane-17beta acyl chloride; (2) enabling the androstane-17beta acyl chloride and 2,5-bis(trifluoromethyl) aniline to generate amide forming reaction in the presence of a hydrogen stripping agent to obtain androstane-17beta-N-(2,5-bis (trifluoromethyl)) benzamide, wherein the acid-binding agent is anhydrous potassium carbonate fine powder. The preparation method disclosed by the invention can be used for simply preparing the androstane-17beta-N-(2,5-bis (trifluoromethyl)) benzamide with low toxicity, high quality, high yield and low cost.
