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7α-Thiomethylspironolactone

December 15, 2023

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7α-Thiomethylspironolactone
Clinical data
Other names7α-TMS; SC-26519; 17α-Hydroxy-7α-(methylthio)-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
Drug classAntimineralocorticoid
Identifiers
  • (7R,8R,9S,10R,13S,14S,17R)-10,13-dimethyl-7-methylsulfanylspiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,5'-oxolane]-2',3-dione
CAS Number
  • 38753-77-4
PubChem CID
  • 162325
ChemSpider
  • 142539
UNII
  • 0YU66JY4WL
ChEMBL
  • ChEMBL3544705
CompTox Dashboard (EPA)
  • DTXSID80959567
Chemical and physical data
FormulaC23H32O3S
Molar mass388.57 g·mol−1
3D model (JSmol)
  • Interactive image
  • C[C@]12CCC(=O)C=C1C[C@H]([C@@H]3[C@@H]2CC[C@]4([C@H]3CC[C@@]45CCC(=O)O5)C)SC
  • InChI=1S/C23H32O3S/c1-21-8-4-15(24)12-14(21)13-18(27-3)20-16(21)5-9-22(2)17(20)6-10-23(22)11-7-19(25)26-23/h12,16-18,20H,4-11,13H2,1-3H3/t16-,17-,18+,20+,21-,22-,23+/m0/s1
  • Key:FWRDLPQBEOKIRE-RJKHXGPOSA-N

7α-Thiomethylspironolactone (7α-TMS; developmental code name SC-26519) is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and the major active metabolite of spironolactone.[1] Other important metabolites of spironolactone include 7α-thiospironolactone (7α-TS; SC-24813), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (SC-9376).[2][3][1][4]

Spironolactone is a prodrug with a short terminal half-life of 1.4 hours.[5][6][7] The active metabolites of spironolactone have extended terminal half-lives of 13.8 hours for 7α-TMS, 15.0 hours for 6β-OH-7α-TMS, and 16.5 hours for canrenone, and accordingly, these metabolites are responsible for the therapeutic effects of the drug.[5][6]

7α-TS and 7α-TMS have been found to possess approximately equivalent affinity for the rat ventral prostate androgen receptor (AR) relative to that of spironolactone.[8] The affinity of 7α-TS, 7α-TMS, and spironolactone for the rat prostate AR is about 3.0 to 8.5% of that of dihydrotestosterone (DHT).[8]

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
Canrenone 155 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.

7α-TMS has been found to account for around 80% of the potassium-sparing effect of spironolactone,[6][9][10] whereas canrenone accounts for the remaining approximate 10 to 25% of the potassium-sparing effect of the drug.[11]

See also edit

References edit

  1. ^ a b Yang J, Young MJ (April 2016). "Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences". Current Opinion in Pharmacology. 27: 78–85. doi:10.1016/j.coph.2016.02.005. PMID 26939027.
  2. ^ Parthasarathy HK, MacDonald TM (March 2007). "Mineralocorticoid receptor antagonists". Current Hypertension Reports. 9 (1): 45–52. doi:10.1007/s11906-007-0009-3. PMID 17362671. S2CID 2090391.
  3. ^ Kolkhof P, Bärfacker L (July 2017). "30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development". The Journal of Endocrinology. 234 (1): T125–T140. doi:10.1530/JOE-16-0600. PMC 5488394. PMID 28634268.
  4. ^ Doggrell SA, Brown L (May 2001). "The spironolactone renaissance". Expert Opinion on Investigational Drugs. 10 (5): 943–954. doi:10.1517/13543784.10.5.943. PMID 11322868. S2CID 39820875.
  5. ^ a b Sica DA (January 2005). "Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis". Heart Failure Reviews. 10 (1): 23–29. doi:10.1007/s10741-005-2345-1. PMID 15947888. S2CID 21437788.
  6. ^ a b c 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.
  7. ^ Aronson JK (2003). "Pharmacological management of heart failure". In Warrel DA, Cox TM, Firth JD, Benz Jr EJ (eds.). Oxford Textbook of Medicine. Vol. 1. Oxford University Press. pp. 1–. ISBN 978-0-19-262922-7.
  8. ^ a b Cutler GB, Pita JC, Rifka SM, Menard RH, Sauer MA, Loriaux DL (July 1978). "SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate". The Journal of Clinical Endocrinology and Metabolism. 47 (1): 171–175. doi:10.1210/jcem-47-1-171. PMID 263288.
  9. ^ International Agency for Research on Cancer; World Health Organization (2001). Some Thyrotropic Agents. World Health Organization. pp. 325–. ISBN 978-92-832-1279-9.
  10. ^ 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.
  11. ^ Angeli P, Gatta A (15 April 2008). "Medical Treatment of Ascites in Cirrhosis" (PDF). 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. doi:10.1002/9780470987476.ch18. ISBN 978-1-4051-4370-7.

Further reading edit

  • 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.
 

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December 15, 2023
thiomethylspironolactone, clinical, dataother, names7α, 26519, 17α, hydroxy, methylthio, oxopregn, carboxylic, acid, lactonedrug, classantimineralocorticoididentifiersiupac, name, dimethyl, methylsulfanylspiro, decahydro, cyclopenta, phenanthrene, oxolane, dio. 7a ThiomethylspironolactoneClinical dataOther names7a TMS SC 26519 17a Hydroxy 7a methylthio 3 oxopregn 4 ene 21 carboxylic acid g lactoneDrug classAntimineralocorticoidIdentifiersIUPAC name 7R 8R 9S 10R 13S 14S 17R 10 13 dimethyl 7 methylsulfanylspiro 2 6 7 8 9 11 12 14 15 16 decahydro 1H cyclopenta a phenanthrene 17 5 oxolane 2 3 dioneCAS Number38753 77 4PubChem CID162325ChemSpider142539UNII0YU66JY4WLChEMBLChEMBL3544705CompTox Dashboard EPA DTXSID80959567Chemical and physical dataFormulaC 23H 32O 3SMolar mass388 57 g mol 13D model JSmol Interactive imageSMILES C C 12CCC O C C1C C H C H 3 C H 2CC C 4 C H 3CC C 45CCC O O5 C SCInChI InChI 1S C23H32O3S c1 21 8 4 15 24 12 14 21 13 18 27 3 20 16 21 5 9 22 2 17 20 6 10 23 22 11 7 19 25 26 23 h12 16 18 20H 4 11 13H2 1 3H3 t16 17 18 20 21 22 23 m0 s1Key FWRDLPQBEOKIRE RJKHXGPOSA N7a Thiomethylspironolactone 7a TMS developmental code name SC 26519 is a steroidal antimineralocorticoid and antiandrogen of the spirolactone group and the major active metabolite of spironolactone 1 Other important metabolites of spironolactone include 7a thiospironolactone 7a TS SC 24813 6b hydroxy 7a thiomethylspironolactone 6b OH 7a TMS and canrenone SC 9376 2 3 1 4 Spironolactone is a prodrug with a short terminal half life of 1 4 hours 5 6 7 The active metabolites of spironolactone have extended terminal half lives of 13 8 hours for 7a TMS 15 0 hours for 6b OH 7a TMS and 16 5 hours for canrenone and accordingly these metabolites are responsible for the therapeutic effects of the drug 5 6 7a TS and 7a TMS have been found to possess approximately equivalent affinity for the rat ventral prostate androgen receptor AR relative to that of spironolactone 8 The affinity of 7a TS 7a TMS and spironolactone for the rat prostate AR is about 3 0 to 8 5 of that of dihydrotestosterone DHT 8 vte Pharmacokinetics of 100 mg day spironolactone and its metabolites Compound Cmax day 1 Cmax day 15 AUC day 15 t1 2Spironolactone 72 ng mL 173 nmol L 80 ng mL 192 nmol L 231 ng hour mL 555 nmol hour L 1 4 hoursCanrenone 155 ng mL 455 nmol L 181 ng mL 532 nmol L 2 173 ng hour mL 6 382 nmol hour L 16 5 hours7a 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 hours6b OH 7a 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 hoursSources See template 7a TMS has been found to account for around 80 of the potassium sparing effect of spironolactone 6 9 10 whereas canrenone accounts for the remaining approximate 10 to 25 of the potassium sparing effect of the drug 11 See also edit7a Thiomethylspironolactone sulfoxide 7a ThioprogesteroneReferences edit a b Yang J Young MJ April 2016 Mineralocorticoid receptor antagonists pharmacodynamics and pharmacokinetic differences Current Opinion in Pharmacology 27 78 85 doi 10 1016 j coph 2016 02 005 PMID 26939027 Parthasarathy HK MacDonald TM March 2007 Mineralocorticoid receptor antagonists Current Hypertension Reports 9 1 45 52 doi 10 1007 s11906 007 0009 3 PMID 17362671 S2CID 2090391 Kolkhof P Barfacker L July 2017 30 YEARS OF THE MINERALOCORTICOID RECEPTOR Mineralocorticoid receptor antagonists 60 years of research and development The Journal of Endocrinology 234 1 T125 T140 doi 10 1530 JOE 16 0600 PMC 5488394 PMID 28634268 Doggrell SA Brown L May 2001 The spironolactone renaissance Expert Opinion on Investigational Drugs 10 5 943 954 doi 10 1517 13543784 10 5 943 PMID 11322868 S2CID 39820875 a b Sica DA January 2005 Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis Heart Failure Reviews 10 1 23 29 doi 10 1007 s10741 005 2345 1 PMID 15947888 S2CID 21437788 a b c 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 Aronson JK 2003 Pharmacological management of heart failure In Warrel DA Cox TM Firth JD Benz Jr EJ eds Oxford Textbook of Medicine Vol 1 Oxford University Press pp 1 ISBN 978 0 19 262922 7 a b Cutler GB Pita JC Rifka SM Menard RH Sauer MA Loriaux DL July 1978 SC 25152 A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha dihydrotestosterone receptor of human and rat prostate The Journal of Clinical Endocrinology and Metabolism 47 1 171 175 doi 10 1210 jcem 47 1 171 PMID 263288 International Agency for Research on Cancer World Health Organization 2001 Some Thyrotropic Agents World Health Organization pp 325 ISBN 978 92 832 1279 9 Agusti G Bourgeois S Cartiser N Fessi H Le Borgne M Lomberget T January 2013 A safe and practical method for the preparation of 7a thioether and thioester derivatives of spironolactone Steroids 78 1 102 107 doi 10 1016 j steroids 2012 09 005 PMID 23063964 S2CID 8992318 Angeli P Gatta A 15 April 2008 Medical Treatment of Ascites in Cirrhosis PDF In Gines P Arroyo V Rodes J Schrier RW eds Ascites and Renal Dysfunction in Liver Disease Pathogenesis Diagnosis and Treatment John Wiley amp Sons p 229 doi 10 1002 9780470987476 ch18 ISBN 978 1 4051 4370 7 Further reading editGardiner 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 nbsp This article about a steroid is a stub You can help Wikipedia by expanding it vte nbsp This drug article relating to the genito urinary system is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title 7a Thiomethylspironolactone amp oldid 1187069962, wikipedia, wiki, book, books, library,

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