Chemistry:Epristeride

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Epristeride, sold under the brand names Aipuliete and Chuanliu, is a medication which is used in the treatment of enlarged prostate in China.[1][2][3] It is taken by mouth.[4]

Epristeride is a 5α-reductase inhibitor and works by decreasing the production of dihydrotestosterone (DHT), an androgen sex hormone, in certain parts of the body like the prostate gland.[5][6][7] It inhibits two of the three forms of 5α-reductase but is of relatively low efficacy and can decrease DHT levels in the blood only by about 25 to 54%.[7]

Epristeride was under development for the treatment of enlarged prostate, scalp hair loss, and acne in the United States and other countries in the 1990s but did not complete development in these countries.[5][2] Instead, it was developed and introduced for the treatment of enlarged prostate in China in 2000.[2]

Medical uses

Epristeride is used in the treatment of benign prostatic hyperplasia (BPH), otherwise known as enlarged prostate.[1][2]

Pharmacology

Pharmacodynamics

Epristeride is a selective, transition-state, non-competitive or uncompetitive, irreversible inhibitor of 5α-reductase,[5][6] and is specific to the type II isoform of the enzyme similarly to finasteride and turosteride but unlike dutasteride.[7]

Epristeride is unique in its mechanism of action relative to finasteride and dutasteride in that it binds irreversibly to 5α-reductase and results in the formation of an unproductive complex of the 5α-reductase enzyme, the substrate testosterone, and the cofactor NADPH.[7][8] For this reason, testosterone is caught in a trap, and it was initially speculated that the reciprocal increase in intraprostatic levels of testosterone seen with finasteride and dutasteride should not happen with epristeride.[7][8] However, subsequent clinical data have not supported this hypothesis.[7] Moreover, in spite of the fact that epristeride is a very potent inhibitor of 5α-reductase type II (0.18–2 nM), it has been found to reduce circulating levels of dihydrotestosterone (DHT) by only 25 to 54% following 8 days of therapy over a dosage range of 0.4 to 160 mg/day.[7] For this reason, relative to other 5α-reductase inhibitors like finasteride and dutasteride, the degree of DHT suppression with epristeride falls short of that desirable for full clinical benefit.[7]

Pharmacokinetics

The oral bioavailability of epristeride is 93%.[9] It has an elimination half-life of 26 hours.[9]

Chemistry

See also: Biology:List of 5α-reductase inhibitors

Epristeride, also known as 17β-(tert-butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid, is a synthetic androstane steroid.

Synthesis

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Oxidation of the acetyl group in progesterone gives the carboxylic acid (1). Halogenation with phosphorus tribromide converts the enone to the enol bromide and the acid to the acyl halide; mild base hydrolyzes the latter back to the free acid, giving (2). Halogenation with oxalyl chloride and a Schotten–Baumann reaction with tert-butylamine yields the amide (3). Epristeride is formed when the bromine atom in this compound is converted to a carboxylic acid via the organolithium intermediate (4).[10][11][12][13]

History

Epristeride was under development for the treatment of BPH, androgenic alopecia (pattern hair loss), and acne vulgaris by SmithKline Beecham (now GlaxoSmithKline) in the 1990s and reached phase III clinical trials in the United States, United Kingdom, and Japan,[5] but ultimately was never marketed in these countries.[2] Instead, epristeride was developed by Ono Pharmaceutical and introduced for the treatment of BPH in China in 2000.[2]

Society and culture

Generic names

Epristeride is the generic name of the drug and its INN, USAN, BAN, and JAN.[3]

Brand names

Epristeride is marketed under the brand names Aipuliete and Chuanliu in China.[3][2]

References

  1. ↑ 1.0 1.1 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 31 October 1999. pp. 113–. ISBN 978-0-7514-0499-9. https://books.google.com/books?id=mqaOMOtk61IC&pg=PA113. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Epristeride". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800002533. 
  3. ↑ 3.0 3.1 3.2 "List of 21 Benign Prostatic Hyperplasia Medications Compared". Drugs.com. https://www.drugs.com/international/epristeride.html. 
  4. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named LiljeforsKrogsgaard-Larsen2003
  5. ↑ 5.0 5.1 5.2 5.3 "Epristeride SmithKline Beecham". IDrugs 1 (1): 152–157. May 1998. PMID 18465521. 
  6. ↑ 6.0 6.1 "Pharmacological and molecular evidence for the expression of the two steroid 5 alpha-reductase isozymes in normal and hyperplastic human prostatic cells in culture". The Prostate 32 (3): 155–163. August 1997. doi:10.1002/(SICI)1097-0045(19970801)32:3<155::AID-PROS1>3.0.CO;2-K. PMID 9254894. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 "Inhibitors of 5 alpha-Reductase". Current Pharmaceutical Design (Bentham Science Publishers) 2 (1): 70–. February 1996. https://books.google.com/books?id=IYn4Va7wtAoC&pg=PA70. 
  8. ↑ 8.0 8.1 "Anti-hormome Therapy: Principles of Endocrine Therapy of Cancer". Cancer. Springer Science & Business Media. 30 January 2007. pp. 49–. ISBN 978-3-540-33120-9. https://books.google.com/books?id=fdtDAAAAQBAJ&pg=PA49. 
  9. ↑ 9.0 9.1 Cite error: Invalid <ref> tag; no text was provided for refs named pmid8983399
  10. ↑ "Inhibition of steroid 5 alpha-reductase by unsaturated 3-carboxysteroids". Journal of Medicinal Chemistry 33 (3): 943–950. March 1990. doi:10.1021/jm00165a010. PMID 2308145. 
  11. ↑ "Improved Syntheses of Epristeride, a Potent Human 5.alpha.-Reductase Inhibitor". The Journal of Organic Chemistry 59 (20): 5987–5989. 1994. doi:10.1021/jo00099a031. 
  12. ↑ "Palladium and Nickel Catalyzed Hydroxycarbonylation of a Steroidal Bromodiene in the Synthesis of Episteride, a Potent 5α-Reductase Inhibitor". Synthetic Communications 28 (9): 1611–1615. 1998. doi:10.1080/00397919808006865. 
  13. ↑ "A practical synthesis of 3-substituted delta 3,5(6)-steroids as new potential 5 alpha-reductase inhibitor". Bioorganic & Medicinal Chemistry Letters 8 (15): 1949–1952. August 1998. doi:10.1016/S0960-894X(98)00339-4. PMID 9873464. 

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