Canrenone

Last updated
Canrenone
Canrenone.svg
Canrenone 3D ball.png
Clinical data
Trade names Contaren, Luvion, Phanurane, Spiroletan
Other namesAldadiene; [1] SC-9376; RP-11614; 7α-Desthioacetyl-δ6-spironolactone; 6,7-Dehydro-7α-desthioacetylspironolactone; 17-Hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone
AHFS/Drugs.com International Drug Names
Drug class Antimineralocorticoid
ATC code
Pharmacokinetic data
Protein binding 95%
Elimination half-life 16.5 hours [2]
Identifiers
  • 10,13-Dimethylspiro[2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-17,5'-oxolane]-2',3-dione
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.012.322 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H28O3
Molar mass 340.463 g·mol−1
3D model (JSmol)
  • O=C5\C=C4\C=C/[C@@H]1[C@H](CC[C@]3([C@H]1CC[C@]32OC(=O)CC2)C)[C@@]4(C)CC5
  • InChI=1S/C22H28O3/c1-20-9-5-15(23)13-14(20)3-4-16-17(20)6-10-21(2)18(16)7-11-22(21)12-8-19(24)25-22/h3-4,13,16-18H,5-12H2,1-2H3/t16-,17+,18+,20+,21+,22-/m1/s1 Yes check.svgY
  • Key:UJVLDDZCTMKXJK-WNHSNXHDSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Canrenone, sold under the brand names Contaren, Luvion, Phanurane, and Spiroletan, is a steroidal antimineralocorticoid [3] [4] of the spirolactone group related to spironolactone which is used as a diuretic in Europe, including in Italy and Belgium. [5] [6] [7] [8] It is also an important active metabolite of spironolactone, and partially accounts for its therapeutic effects. [9] [2]

Contents

Medical uses

Canrenone is mainly used as a diuretic.[ citation needed ]

Canrenone has been found to be effective in the treatment of hirsutism in women. [10]

Heart failure

Two studies of canrenone in people with heart failure have shown a mortality benefit compared to placebo. In the evaluation which studied people with chronic heart failure (CHF), people that were treated with canrenone displayed a lower number of deaths compared to the placebo group, indicating a death and morbidity benefit of the medication.

One study compared 166 treated with canrenone to 336 given conventional therapy lasting 10 years. Differences in systolic and diastolic blood pressure was observed between both patient groups where, patients treated with canrenone, showed a lower blood pressure compared to conventional therapy. Uric acid was lower in the group treated with canrenone; however, no differences were seen in potassium, sodium, and brain natriuretic peptide (BNP) levels. Left ventricular mass was also lower in the group treated with canrenone and a greater progression of NYHA class was observed in the control group compared to patients treated with canrenone. [11]

Another study concluded that treatment with canrenone in patients with chronic heart failure improves diastolic function and further decreased BNP levels. [12]

Pharmacology

Pharmacodynamics

Canrenone is reportedly more potent as an antimineralocorticoid relative to spironolactone, but is considerably less potent and effective as an antiandrogen. [13] [14] Similarly to spironolactone, canrenone inhibits steroidogenic enzymes such as 11β-hydroxylase, cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 17,20-lyase, and 21-hydroxylase, but once again, is comparatively less potent in doing so. [15]

Pharmacokinetics

The elimination half-life of canrenone is about 16.5 hours. [2]

As a metabolite

Canrenone is an active metabolite of spironolactone, canrenoic acid, and potassium canrenoate, and is considered to be partially responsible for their effects. [9] It has been found to have approximately 10 to 25% of the potassium-sparing diuretic effect of spironolactone, [16] whereas another metabolite, 7α-thiomethylspironolactone (7α-TMS), accounts for around 80% of the potassium-sparing effect of the drug. [17] [18] [19]

Pharmacokinetics of 100 mg/day spironolactone and its metabolites
Compound Cmax (day 1) Cmax (day 15) AUC (day 15) t1/2
Spironolactone 72 ng/mL (173 nmol/L)80 ng/mL (192 nmol/L)231 ng•hour/mL (555 nmol•hour/L)1.4 hours
Canrenone155 ng/mL (455 nmol/L)181 ng/mL (532 nmol/L)2,173 ng•hour/mL (6,382 nmol•hour/L)16.5 hours
7α-TMS 359 ng/mL (924 nmol/L)391 ng/mL (1,006 nmol/L)2,804 ng•hour/mL (7,216 nmol•hour/L)13.8 hours
6β-OH-7α-TMS 101 ng/mL (250 nmol/L)125 ng/mL (309 nmol/L)1,727 ng•hour/mL (4,269 nmol•hour/L)15.0 hours
Sources: See template.

History

Canrenone was described and characterized in 1959. [5] It was introduced for medical use, in the form of potassium canrenoate (the potassium salt of canrenoic acid), by 1968. [20]

Society and culture

Generic names

Canrenone is the INN and USAN of the drug. [6] [8]

Brand names

Canrenone has been marketed under the brand names Contaren, Luvion, Phanurane, and Spiroletan, among others. [5] [8] [20]

Availability

Canrenone appears to remain available only in Italy, although potassium canrenoate remains marketed in various other countries as well. [21] [22]

See also

Related Research Articles

<span class="mw-page-title-main">Spironolactone</span> Steroidal antiandrogen and antimineralocorticoid

Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women, and as a part of feminizing hormone therapy in trans women. Spironolactone is taken by mouth.

<span class="mw-page-title-main">Amiloride</span> Medication

Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.

<span class="mw-page-title-main">Potassium-sparing diuretic</span> Drugs that cause diuresis without causing potassium loss in the urine and leading to hyperkalemia

Potassium-sparing diuretics refers to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone antagonists can also be used for treatment of primary hyperaldosteronism. Spironolactone, a steroidal aldosterone antagonist, is also used in management of female hirsutism and acne from PCOS or other causes.

<span class="mw-page-title-main">Mineralocorticoid receptor antagonist</span> Drug class

A mineralocorticoid receptor antagonist or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive therapy, in combination with other drugs, for the management of chronic heart failure. Spironolactone, the first member of the class, is also used in the management of hyperaldosteronism and female hirsutism. Most antimineralocorticoids, including spironolactone, are steroidal spirolactones. Finerenone is a nonsteroidal antimineralocorticoid.

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

Eplerenone, sold under the brand name Inspra, is an aldosterone antagonist type of potassium-sparing diuretic that is used to treat chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to elevated aldosterone. It is a steroidal antimineralocorticoid of the spirolactone group and a selective aldosterone receptor antagonist (SARA). Eplerenone is more selective than spironolactone at the mineralocorticoid receptor relative to binding at androgen, progestogen, glucocorticoid, or estrogen receptors.

<span class="mw-page-title-main">Potassium canrenoate</span> Pharmaceutical drug

Potassium canrenoate or canrenoate potassium (USAN), also known as aldadiene kalium, the potassium salt of canrenoic acid, is an aldosterone antagonist of the spirolactone group. Like spironolactone, it is a prodrug, and is metabolized to active canrenone in the body.

<span class="mw-page-title-main">Spirolactone</span>

Spirolactones are a class of functional group in organic chemistry featuring a cyclic ester attached spiro to another ring system. The name is also used to refer to a class of synthetic steroids, called steroid-17α-spirolactones, 17α-spirolactosteroids, or simply 17α-spirolactones, which feature their spirolactone group at the C17α position. They are antimineralocorticoids, or antagonists of the mineralocorticoid receptor, and have been employed clinically as potassium-sparing diuretics. Some also possess progestogenic and/or antiandrogen properties, which have both contributed to side effects and been utilized for medical indications. The spirolactones were developed by G. D. Searle & Company in the 1950s and thereafter and were denoted as "SC" compounds.

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

Benorterone, also known by its developmental code name SKF-7690 and as 17α-methyl-B-nortestosterone, is a steroidal antiandrogen which was studied for potential medical use but was never marketed. It was the first known antiandrogen to be studied in humans. It is taken by mouth or by application to skin.

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

Prorenone is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone that was never marketed. It is the lactonic form of prorenoic acid (prorenoate), and prorenoate potassium (SC-23992), the potassium salt of prorenoic acid, also exists. Prorenoate potassium is about 8 times more potent than spironolactone as an antimineralocorticoid in animals, and it may act as a prodrug to prorenone. In addition to the mineralocorticoid receptor, prorenone also binds to the glucocorticoid, androgen, and progesterone receptors. The antiandrogenic potency of prorenone in vivo in animals is close to that of spironolactone. Similarly to spironolactone, prorenone is also a potent inhibitor of aldosterone biosynthesis.

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

Mexrenone is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone that was never marketed. It is the lactonic form of mexrenoic acid (mexrenoate), and mexrenoate potassium (SC-26714), the potassium salt of mexrenoic acid, also exists. In addition to the mineralocorticoid receptor, mexrenone also binds to the glucocorticoid, androgen, and progesterone receptors. Relative to spironolactone, it has markedly reduced antiandrogen activity. Eplerenone is the 9-11α-epoxy analogue of mexrenone.

<span class="mw-page-title-main">SC-5233</span> Chemical compound

SC-5233, also known as 6,7-dihydrocanrenone or 20-spirox-4-ene-3,20-dione, is a synthetic, steroidal antimineralocorticoid of the spirolactone group which was developed by G. D. Searle & Company in the 1950s but was never marketed. It was the first synthetic antagonist of the mineralocorticoid receptor to have been identified and tested in humans. The drug was found to lack appreciable oral bioavailability and to be of low potency when administered parenterally, but it nonetheless produced a mild diuretic effect in patients with congestive heart failure. SC-8109, the 19-nor (19-demethyl) analogue, was developed and found to have improved oral bioavailability and potency, but still had low potency. Spironolactone followed and had both good oral bioavailability and potency, and was the first synthetic antimineralocorticoid to be marketed. It has about 46-fold higher oral potency than SC-5233.

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

Mespirenone (INN), also known as Δ1-15β,16β-methylenespironolactone, is a steroidal antimineralocorticoid of the spirolactone group related to spironolactone that was never marketed. Animal research found that it was 3.3-fold more potent as an antimineralocorticoid relative to spironolactone. In addition to its antimineralocorticoid properties, mespirenone is also a progestogen, antigonadotropin, and antiandrogen. It is 2- to 3-fold as potent as spironolactone as a progestogen and antigonadotropin but its antiandrogenic activity is markedly reduced and weak in comparison. Mespirenone is also a potent and specific enzyme inhibitor of 18-hydroxylase and thus of mineralocorticoid biosynthesis. The drug was under development by Schering and reached phase II clinical trials but was discontinued in 1989.

<span class="mw-page-title-main">SC-8109</span> Chemical compound

SC-8109 is a steroidal antimineralocorticoid of the spirolactone group which was never marketed. It is a potent antagonist of the mineralocorticoid receptor and is more potent than the related drug SC-5233. However, SC-8109 was found to have relatively low oral bioavailability and potency, though it nonetheless produced a mild diuretic effect in patients with congestive heart failure. Spironolactone, another spirolactone, followed and had both good oral bioavailability and potency, and was the first antimineralocorticoid to be marketed.

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

Spiroxasone is a synthetic, steroidal antimineralocorticoid of the spirolactone group which was developed as a diuretic and antihypertensive agent but was never marketed. It was synthesized and assayed in 1963. The drug is 7α-acetylthiospirolactone with the ketone group removed from the C17α spirolactone ring. Similarly to other spirolactones like spironolactone, spiroxasone also possesses antiandrogen activity.

<span class="mw-page-title-main">7α-Thiomethylspironolactone</span> Chemical compound

←

<span class="mw-page-title-main">6β-Hydroxy-7α-thiomethylspironolactone</span> Chemical compound

6β-Hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS) is a steroidal antimineralocorticoid of the spirolactone group and a major active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiospironolactone, 7α-thiomethylspironolactone, and canrenone (SC-9376).

<span class="mw-page-title-main">7α-Thiospironolactone</span> Chemical compound

7α-Thiospironolactone is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and a minor active metabolite of spironolactone. Other important metabolites of spironolactone include 7α-thiomethylspironolactone, 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (SC-9376).

<span class="mw-page-title-main">7α-Thioprogesterone</span> Chemical compound

7α-Thioprogesterone is a synthetic, steroidal, and potent antimineralocorticoid (putative) and antiandrogen which was developed by G. D. Searle & Co and was described in the late 1970s and early 1980s but was never developed or introduced for medical use. It is a derivative of progesterone (pregn-4-ene-3,20-dione) with a thio (sulfur) substitution at the C7α position, and is related to the spirolactone group of drugs but lacks a γ-lactone ring.

<span class="mw-page-title-main">Pharmacodynamics of spironolactone</span> Mechanisms of action

The pharmacodynamics of spironolactone, an antimineralocorticoid and antiandrogen medication, concern its mechanisms of action, including its biological targets and activities, as well as its physiological effects. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase estradiol and cortisol levels and hence could have slight indirect estrogenic and glucocorticoid effects. The medication has also been found to interact very weakly with the estrogen and progesterone receptors, and to act as an agonist of the pregnane X receptor. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.

<span class="mw-page-title-main">7α-Thiomethylspironolactone sulfoxide</span> Chemical compound

7α-Thiomethylspironolactone sulfoxide is a metabolite of spironolactone, an antimineralocorticoid and antiandrogen medication. 7α-TMS sulfoxide is specifically formed from 7α-thiomethylspironolactone (7α-TMS).

References

  1. ↑ Müller J (6 December 2012). Regulation of Aldosterone Biosynthesis: Physiological and Clinical Aspects. Springer Science & Business Media. pp. 164–. ISBN   978-3-642-83120-1.
  2. 1 2 3 Gardiner P, Schrode K, Quinlan D, Martin BK, Boreham DR, Rogers MS, et al. (April 1989). "Spironolactone metabolism: steady-state serum levels of the sulfur-containing metabolites". Journal of Clinical Pharmacology. 29 (4): 342–347. doi:10.1002/j.1552-4604.1989.tb03339.x. PMID   2723123. S2CID   29457093.
  3. ↑ Losert W, Casals-Stenzel J, Buse M (1985). "Progestogens with antimineralocorticoid activity". Arzneimittel-Forschung. 35 (2): 459–471. PMID   4039568.
  4. ↑ Fernandez MD, Carter GD, Palmer TN (January 1983). "The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol". British Journal of Clinical Pharmacology. 15 (1): 95–101. doi:10.1111/j.1365-2125.1983.tb01470.x. PMC   1427833 . PMID   6849751.
  5. 1 2 3 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 210–. ISBN   978-1-4757-2085-3.
  6. 1 2 Hill R, Makin H, Kirk D, Murphy G (23 May 1991). Dictionary of Steroids. CRC Press. pp. 656–. ISBN   978-0-412-27060-4.
  7. ↑ Romanelli RG, Gentilini P (May 2004). "Cross reactivity due to positive canrenone interference". Gut. 53 (5): 772–773. PMC   1774040 . PMID   15082604.
  8. 1 2 3 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 167–. ISBN   978-3-88763-075-1.
  9. 1 2 Clark MA, Harvey RA, Finkel R, Rey JA, Whalen K (15 December 2011). Pharmacology. Lippincott Williams & Wilkins. pp. 286–. ISBN   978-1-4511-1314-3.
  10. ↑ Sobbrio GA, Granata A, Panacea A, Trimarchi F (1989). "Effectiveness of short term canrenone treatment in idiopathic hirsutism". Minerva Endocrinologica. 14 (2): 105–108. PMID   2761494.
  11. ↑ Derosa G, Maffioli P, Scelsi L, Bestetti A, Vanasia M, Cicero AF, et al. (March 2019). "Canrenone on cardiovascular mortality in congestive heart failure: CanrenOne eFFects on cardiovascular mortality in patiEnts with congEstIve hearT failure: The COFFEE-IT study". Pharmacological Research. 141: 46–52. doi:10.1016/j.phrs.2018.11.037. PMID   30502530. S2CID   54564252.
  12. ↑ de Simone G, Chinali M, Mureddu GF, Cacciatore G, Lucci D, Latini R, et al. (October 2011). "Effect of canrenone on left ventricular mechanics in patients with mild systolic heart failure and metabolic syndrome: the AREA-in-CHF study". Nutrition, Metabolism, and Cardiovascular Diseases. 21 (10): 783–791. doi:10.1016/j.numecd.2010.02.012. PMID   21939839.
  13. ↑ Coelingh Benni H, Vemer H (15 December 1990). Chronic Hyperandrogenic Anovulation. CRC Press. pp. 152–. ISBN   978-1-85070-322-8.
  14. ↑ Seldin DW, Giebisch GH (23 September 1997). Diuretic Agents: Clinical Physiology and Pharmacology. Academic Press. pp. 630–. ISBN   978-0-08-053046-8.
  15. ↑ Colby HD (April 1981). "Chemical suppression of steroidogenesis". Environmental Health Perspectives. 38: 119–127. doi:10.1289/ehp.8138119. PMC   1568425 . PMID   6786868.
  16. ↑ Angeli P, Gatta A (15 April 2008). "Medical Treatment of Ascites in Cirrhosis". In Ginés P, Arroyo V, Rodés J, Schrier RW (eds.). Ascites and Renal Dysfunction in Liver Disease: Pathogenesis, Diagnosis, and Treatment. John Wiley & Sons. p. 229. ISBN   978-1-4051-4370-7.
  17. ↑ Maron BA, Leopold JA (September 2008). "Mineralocorticoid receptor antagonists and endothelial function". Current Opinion in Investigational Drugs. 9 (9): 963–969. PMC   2967484 . PMID   18729003.
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  19. ↑ Agusti G, Bourgeois S, Cartiser N, Fessi H, Le Borgne M, Lomberget T (January 2013). "A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone". Steroids. 78 (1): 102–107. doi:10.1016/j.steroids.2012.09.005. PMID   23063964. S2CID   8992318.
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  21. ↑ "List of Aldosterone receptor antagonists". Drugs.com.
  22. ↑ "Potassium Uses, Side Effects & Interactions". Drugs.com.
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