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Alfuzosin

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Alfuzosin
Clinical data
Pronunciation/ælˈfjuːzoʊsɪn/ al-FEW-zoh-sin
Trade namesUroxatral, others
AHFS/Drugs.comMonograph
MedlinePlusa64002
License data
Pregnancy
category
  • AU: B2
Routes of
administration		By mouth
Drug classα1 blocker
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability49%
Protein binding82–90%
MetabolismLiver (CYP3A4-mediated)
Elimination half-life10 hours
ExcretionFeces (69%) and Urine (24%)
Identifiers
  • (RS)-N-[3-[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)- methyl-amino]propyl] tetrahydrofuran- 2-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.108.671 Edit this at Wikidata
Chemical and physical data
FormulaC19H27N5O4
Molar mass389.456 g·mol−1
3D model (JSmol)
  • O=C(NCCCN(c2nc1cc(OC)c(OC)cc1c(n2)N)C)C3OCCC3
  • InChI=1S/C19H27N5O4/c1-24(8-5-7-21-18(25)14-6-4-9-28-14)19-22-13-11-16(27-3)15(26-2)10-12(13)17(20)23-19/h10-11,14H,4-9H2,1-3H3,(H,21,25)(H2,20,22,23) checkY
  • Key:WNMJYKCGWZFFKR-UHFFFAOYSA-N checkY
  (verify)

Alfuzosin, sold under the brand name Uroxatral among others, is a medication of the α1 blocker class. It is used to treat benign prostatic hyperplasia (BPH).[1]

As an antagonist of the α1-adrenergic receptor, it works by relaxing the muscles in the prostate and bladder neck, making urination easier.

Clinical information

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Side effects

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The most common side effects are dizziness (due to postural hypotension), upper respiratory tract infection, headache, fatigue, and abdominal disturbances. Side effects include stomach pain, heartburn, and congested nose.[2] Adverse effects of alfuzosin are similar to that of tamsulosin, but with 70% lower rate of retrograde ejaculation.[3]

Indications for use

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The drug is indicated for the treatment of symptoms associated with benign prostatic hyperplasia. It has no effect on prostate size.

Contraindications

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Administration is contraindicated in patients with severe hepatic impairment or arterial hypotension (low blood pressure), as well as in those undergoing treatment with other alpha blockers.[4]

Pharmacological properties

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As an antagonist, alfuzosin selectively binds to postsynaptic Α1-adrenoceptors, leading to relaxation of the smooth muscle in the prostate and urethra. This increases uroflowmetry and facilitates micturition. The bioavailability is 64%, and the plasma half-life is 4 to 6 hours. The maximum plasma concentration is reached after approximately 90 minutes.[4]

Chemistry

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Alfuzosin contains a stereocenter, so is chiral, with two enantiomeric forms, (R)- and (S)-alfuzosin. The drug is used as a racemate, (RS)-alfuzosin, a 1:1 mixture of the (R)- and (S)- forms.[5]

Enantiomers of alfuzosin
Strukturformel des (R)-Enantiomers
CAS number: 123739-69-5 		Strukturformel des (S)-Enantiomers
CAS number.: 123739-70-8

It is provided as the hydrochloride salt.

Society and culture

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History

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Alfuzosin was patented in 1979 and first developed as an antihypertensive agent in 1982 by Sanofi-Synthélabo (now Sanofi).[6] It was approved for medical use in 1988.[7] It was approved in the US for benign prostatic hyperplasia in 2003. In 2020, it was the 336th-most commonly prescribed medication in the United States, with more than 700,000 prescriptions.[8][9]

Brand names

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It is sold under the brand names Alfosoft, Uroxatral,[10] Xatral, Prostetrol,[11] and Alfural.[12][unreliable source?]

Synthesis

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The nitration of veratraldehyde (1) gives 6-Nitroveratraldehyde [20357-25-9] (2). Oxidation of the aldehyde to the acid, halogenation with thionyl chloride and amide formation with ammonia gives 4,5-dimethoxy-2-nitrobenzamide [4959-60-8] (3). Béchamp reduction of the nitro group gives 2-amino-4,5-dimethoxybenzamide [5004-88-6] (4). Reaction with urea leads to 6,7-Dimethoxyquinazoline-2,4-dione [28888-44-0] (5). Halogenation with phosphoryl chloride gives 2,4-Dichloro-6,7-dimethoxyquinazoline [27631-29-4] (6). Treatment with one equivalent of ammonia yields 4-Amino-2-chloro-6,7-dimethoxyquinazoline [23680-84-4] (7).

Thieme ChemDrug Synthesis:[13][14] Patent:[15] New patent:[16] Radiolabelled:[17]

The reaction of 2-tetrahydrofuroic acid [16874-33-2] (8) with ethyl chloroformate (9) gives ethoxycarbonyl oxolane-2-carboxylate, PC10997775 (10). Treatment of the mixed anhydride with 3-Methylaminopropionitrile [693-05-0] (11) gives N-(2-Cyanoethyl)tetrahydro-N-methyl-2-furancarboxamide [72104-44-0] (12). Catalytic hydrogenation gives N-(3-Aminopropyl)tetrahydro-N-methyl-2-furancarboxamide [72104-45-1] (13). Migration of the amide methyl group to the terminal position gives N-[3-(methylamino)propyl]oxolane-2-carboxamide [81403-67-0] (14). Convergent synthesis between the two counterparts completed the synthesis of Alfuzosin (15).

References

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  1. ^ Lepor H (August 2016). "Alpha-blockers for the Treatment of Benign Prostatic Hyperplasia". The Urologic Clinics of North America. 43 (3): 311–23. doi:10.1016/j.ucl.2016.04.009. PMC 2213889. PMID 27476124.
  2. ^ "Alfuzosin". MedlinePlus. United States National Library of Medicine. 15 April 2016.
  3. ^ Liu C, Zeng G, Kang R, Wu W, Li J, Chen K, Wan SP (2015). "Efficacy and Safety of Alfuzosin as Medical Expulsive Therapy for Ureteral Stones: A Systematic Review and Meta-Analysis". PLOS ONE. 10 (8) e0134589. Bibcode:2015PLoSO..1034589L. doi:10.1371/journal.pone.0134589. PMC 4526635. PMID 26244843. This article incorporates text available under the CC BY 4.0 license.
  4. ^ a b Michael C. Truß, Christian G. Stief, Stefan Machtens, Till Wagner, Udo Jonas: Pharmakotherapie in der Urologie. 2., vollständig überarbeitete Auflage. Springer, Heidelberg 2005, ISBN 3-540-23449-7, S. 302 ff.
  5. ^ Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 - Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, S. 159, ISBN 978-3-946057-10-9.
  6. ^ Entry on Alfuzosin. at: Römpp Online. Georg Thieme Verlag, retrieved {{{Datum}}}.
  7. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 455. ISBN 978-3-527-60749-5.
  8. ^ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  9. ^ "Alfuzosin - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  10. ^ "Alfuzosin (Oral Route) Description and Brand Names - Mayo Clinic". www.mayoclinic.org. Retrieved 21 September 2022.
  11. ^ "Prostetrol 10mg 30 tablet". royalph.com. Retrieved 21 September 2022.
  12. ^ "Γαληνός - Φάρμακο - ALFURAL". www.galinos.gr (in Greek). Retrieved 21 September 2022.
  13. ^ Cazor, JL; Borg, F.; Dimsdale, M.; Alfuzosin hydrochloride. Drugs Fut 1986, 11, 10, 821.
  14. ^ Manoury, Philippe M.; Binet, Jean L.; Dumas, Andre P.; Lefevre-Borg, Francoise; Cavero, Icilio (1986). "Synthesis and antihypertensive activity of a series of 4-amino-6,7-dimethoxyquinazoline derivatives". Journal of Medicinal Chemistry 29 (1): 19–25. doi:10.1021/jm00151a003.
  15. ^ Philippe M. Manoury, US4315007 (1982 to Synthelabo SA); CA, 96, 162737e.
  16. ^ Keshav Deo, et al. WO2009001369 (to Alembic Ltd.).
  17. ^ Allen, J. (November 1983). "A synthesis of [ 14 C]alfuzosine hydrochloride". Journal of Labelled Compounds and Radiopharmaceuticals. 20 (11): 1283–1286. doi:10.1002/jlcr.2580201109.
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