Epristeride

Last updated
Epristeride
Epristeride.svg
Clinical data
Trade names Aipuliete, Chuanliu
Other namesONO-9302; SKF-105657; 17β-(tert-Butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid
Routes of
administration 		By mouth [1]
Drug class 5α-Reductase inhibitor
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 93% [2]
Elimination half-life 26 hours [2]
Identifiers
  • (8S,9S,10R,13S,14S,17S)-17-(tert-butylcarbamoyl)-10,13-dimethyl-2,7,8,9,11,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthrene-3-carboxylic acid
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C25H37NO3
Molar mass 399.575 g·mol−1
3D model (JSmol)
  • CC(C)(C)NC(=O)C1CCC2C3C\C=C4\C=C(/CCC4(C)C3CCC12C)C(O)=O
  • InChI=1S/C25H37NO3/c1-23(2,3)26-21(27)20-9-8-18-17-7-6-16-14-15(22(28)29)10-12-24(16,4)19(17)11-13-25(18,20)5/h6,14,17-20H,7-13H2,1-5H3,(H,26,27)(H,28,29)
  • Key:VAPSMQAHNAZRKC-UHFFFAOYSA-N

Epristeride, sold under the brand names Aipuliete and Chuanliu, is a medication which is used in the treatment of enlarged prostate in China. [3] [4] [5] It is taken by mouth. [1]

Contents

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. [6] [7] [8] 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%. [8]

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. [6] [4] Instead, it was developed and introduced for the treatment of enlarged prostate in China in 2000. [4]

Medical uses

Epristeride is used in the treatment of benign prostatic hyperplasia (BPH), otherwise known as enlarged prostate. [3] [4]

Pharmacology

Pharmacodynamics

Epristeride is a selective, transition-state, non-competitive or uncompetitive, irreversible inhibitor of 5α-reductase, [6] [7] and is specific to the type II isoform of the enzyme similarly to finasteride and turosteride but unlike dutasteride. [8]

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. [8] [9] 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. [8] [9] However, subsequent clinical data have not supported this hypothesis. [8] 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. [8] 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. [8]

Pharmacokinetics

The oral bioavailability of epristeride is 93%. [2] It has an elimination half-life of 26 hours. [2]

Chemistry

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

Synthesis

Epristeride synthesis.svg

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, [6] but ultimately was never marketed in these countries. [4] Instead, epristeride was developed by Ono Pharmaceutical and introduced for the treatment of BPH in China in 2000. [4]

Society and culture

Generic names

Epristeride is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name. [5]

Brand names

Epristeride is marketed under the brand names Aipuliete and Chuanliu in China. [5] [4]

Related Research Articles

<span class="mw-page-title-main">5α-Reductase 2 deficiency</span> Medical condition

5α-Reductase 2 deficiency (5αR2D) is an autosomal recessive condition caused by a mutation in SRD5A2, a gene encoding the enzyme 5α-reductase type 2 (5αR2). The condition is rare, affects only genetic males, and has a broad spectrum.

<span class="mw-page-title-main">Benign prostatic hyperplasia</span> Noncancerous increase in size of the prostate gland

Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss of bladder control. Complications can include urinary tract infections, bladder stones, and chronic kidney problems.

<span class="mw-page-title-main">Dihydrotestosterone</span> Human hormone

Dihydrotestosterone is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production of sebum and body hair composition.

<span class="mw-page-title-main">Finasteride</span> Antiandrogen medication

Finasteride, sold under the brand names Proscar and Propecia among others, is a medication used to treat pattern hair loss and benign prostatic hyperplasia (BPH) in men. It can also be used to treat excessive hair growth in women. It is usually taken orally but there are topical formulations for patients with hair loss, designed to minimize systemic exposure by acting specifically on hair follicles.

5α-Reductase Enzyme family

5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes of 5α-reductase encoded by the genes SRD5A1, SRD5A2, and SRD5A3.

<span class="mw-page-title-main">5α-Reductase inhibitor</span> Class of medications

5α-Reductase inhibitors (5-ARIs), also known as dihydrotestosterone (DHT) blockers, are a class of medications with antiandrogenic effects which are used primarily in the treatment of enlarged prostate and scalp hair loss. They are also sometimes used to treat excess hair growth in women and as a component of hormone therapy for transgender women.

<span class="mw-page-title-main">Dutasteride</span> Hormone replacement medication

Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before benefits occur. It is also used for scalp hair loss in men and as a part of hormone therapy in transgender women. It is usually taken by mouth.

<span class="mw-page-title-main">SRD5A2</span> Protein-coding gene in the species Homo sapiens

The human gene SRD5A2 encodes the 3-oxo-5α-steroid 4-dehydrogenase 2 enzyme, also known as 5α-reductase type 2 (5αR2), one of three isozymes of 5α-reductase.

<span class="mw-page-title-main">SRD5A1</span> Protein-coding gene in the species Homo sapiens

3-Oxo-5α-steroid 4-dehydrogenase 1 is an enzyme that in humans is encoded by the SRD5A1 gene. It is one of three forms of steroid 5α-reductase.

<span class="mw-page-title-main">Turosteride</span> Chemical compound

Turosteride (FCE-26,073) is a selective inhibitor of the enzyme 5α-reductase which was under investigation by GlaxoSmithKline for the treatment of benign prostatic hyperplasia (BPH), but was never marketed. Similarly to finasteride, turosteride is selective for the type II isoform of 5α-redcutase, with about 15-fold selectivity for it over type I isoform of the enzyme. In animal studies it has been shown to inhibit prostate size and retard tumor growth. It may also be useful for the treatment of acne and hair loss.

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones. They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids. They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.

<span class="mw-page-title-main">BOMT</span> Chemical compound

BOMT, also known by its developmental code name Ro 7-2340 and as 6α-bromo-4-oxa-17α-methyl-5α-dihydrotestosterone, is a synthetic steroidal antiandrogen which was first produced in 1970 and was never marketed for medical use. It is the 6α-brominated, 4-oxygenated, and 17α-methylated derivative of the androgen dihydrotestosterone (DHT). Along with benorterone, cyproterone, and flutamide, BOMT was among the earliest antiandrogens to be developed and extensively studied, although it is less well-documented in comparison to the others. BOMT has been investigated clinically in the treatment of benign prostatic hyperplasia, though development for this use did not continue. There was also interest in BOMT for the potential applications of acne, pattern hair loss, and possibly prostate cancer, but it was not developed for these indications either.

<span class="mw-page-title-main">5α-Dihydronandrolone</span> Chemical compound

5α-Dihydronandrolone is a naturally occurring anabolic–androgenic steroid (AAS) and a 5α-reduced derivative of nandrolone (19-nortestosterone). It is a major metabolite of nandrolone and is formed from it by the actions of the enzyme 5α-reductase analogously to the formation of dihydrotestosterone (DHT) from testosterone.

An androgen synthesis inhibitor is a type of drug which inhibits the enzymatic synthesis of androgens, such as testosterone and dihydrotestosterone (DHT). They include:

<span class="mw-page-title-main">Androstanolone</span> Androgenic and anabolic steroid medication

Androstanolone, or stanolone, also known as dihydrotestosterone (DHT) and sold under the brand name Andractim among others, is an androgen and anabolic steroid (AAS) medication and hormone which is used mainly in the treatment of low testosterone levels in men. It is also used to treat breast development and small penis in males. Compared to testosterone, androstanolone (DHT) is less likely to aromatize into estrogen, and therefore it shows less pronounced estrogenic side effects, such as gynecomastia and water retention. On the other hand, androstanolone (DHT) show more significant androgenic side effects, such as acne, hair loss and prostate enlargement.

<span class="mw-page-title-main">MK-386</span> Chemical compound

MK-386, also known as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, is a synthetic, steroidal 5α-reductase inhibitor which was first reported in 1994 and was never marketed. It is a 4-azasteroid and a potent and selective inhibitor of 5α-reductase type I and shows high selectivity for inhibition of human 5α-reductase type I over 5α-reductase type II, with IC50 values of 0.9 nM and 154 nM, respectively. The drug was under investigation for potential treatment of androgen-dependent conditions such as acne and pattern hair loss (androgenic alopecia or baldness), but was discontinued in early clinical trials due to observations of hepatotoxicity such as elevated liver enzymes.

This article is about the discovery and development of 5α-reductase inhibitors (5-ARIs), also known as dihydrotestosterone (DHT) blockers.

<span class="mw-page-title-main">MK-434</span> Chemical compound

MK-434 is a 5α-reductase inhibitor which was under development in the 1990s by Merck & Co for the treatment of a variety of androgen-dependent conditions including benign prostatic hyperplasia, prostate cancer, pattern hair loss, excessive hair growth, acne, and seborrhea but was never marketed. It acts as a selective inhibitor of 5α-reductase type 2. The drug has been found to decrease circulating dihydrotestosterone levels by a maximum of approximately 50% in men. MK-434 is a synthetic 4-azasteroid and is structurally related to other 5α-reductase inhibitors like finasteride.

References

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  4. 1 2 3 4 5 6 7 "Epristeride". AdisInsight. Springer Nature Switzerland AG.
  5. 1 2 3 "List of 21 Benign Prostatic Hyperplasia Medications Compared". Drugs.com.
  6. 1 2 3 4 Hedge SS (May 1998). "Epristeride SmithKline Beecham". IDrugs. 1 (1): 152–157. PMID   18465521.
  7. 1 2 Berthaut I, Mestayer C, Portois MC, Cussenot O, Mowszowicz I (August 1997). "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. doi:10.1002/(SICI)1097-0045(19970801)32:3<155::AID-PROS1>3.0.CO;2-K. PMID   9254894. S2CID   19849292.
  8. 1 2 3 4 5 6 7 8 Frye SV (February 1996). "Inhibitors of 5 alpha-Reductase". Current Pharmaceutical Design. 2 (1). Bentham Science Publishers: 70–.
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  10. ↑ Holt DA, Levy MA, Oh HJ, Erb JM, Heaslip JI, Brandt M, et al. (March 1990). "Inhibition of steroid 5 alpha-reductase by unsaturated 3-carboxysteroids". Journal of Medicinal Chemistry. 33 (3): 943–950. doi:10.1021/jm00165a010. PMID   2308145.
  11. ↑ Baine NH, Owings FF, Kline DN, Resnick T, Ping LJ, Fox M, et al. (1994). "Improved Syntheses of Epristeride, a Potent Human 5.alpha.-Reductase Inhibitor". The Journal of Organic Chemistry. 59 (20): 5987–5989. doi:10.1021/jo00099a031.
  12. ↑ McGuire MA, Sorenson E, Klein DN, Baine NH (1998). "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. doi:10.1080/00397919808006865.
  13. ↑ Tian W, Zhu Z, Liao Q, Wu Y (August 1998). "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. doi:10.1016/S0960-894X(98)00339-4. PMID   9873464.
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