Alfuzosin

Clinical information

Side effects

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. Adverse effects of alfuzosin are similar to that of tamsulosin, but with 70% lower rate of retrograde ejaculation.

Indications for use

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

Contraindications

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.

Pharmacological properties

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.

Chemistry

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.

It is provided as the hydrochloride salt.

Society and culture

History

Alfuzosin was patented in 1979 and first developed as an antihypertensive agent in 1982 by Sanofi-Synthélabo (now Sanofi). It was approved for medical use in 1988. 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.

Brand names

It is sold under the brand names Alfosoft, Uroxatral, Xatral, Prostetrol, and Alfural.

Synthesis

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).

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

References

1. (August 2016). "Alpha-blockers for the Treatment of Benign Prostatic Hyperplasia". The Urologic Clinics of North America.
2. (15 April 2016). "Alfuzosin". [[MedlinePlus]].
3. (2015). "Efficacy and Safety of Alfuzosin as Medical Expulsive Therapy for Ureteral Stones: A Systematic Review and Meta-Analysis". PLOS ONE.
4. 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. {{RömppOnline
7. (2006). "Analogue-based Drug Discovery". John Wiley & Sons.
8. "The Top 300 of 2020".
9. "Alfuzosin - Drug Usage Statistics".
10. "Alfuzosin (Oral Route) Description and Brand Names - Mayo Clinic".
11. "Prostetrol 10mg 30 tablet".
12. "Γαληνός - Φάρμακο - ALFURAL".
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.