7α-Thiomethylspironolactone

7α-Thiomethylspironolactone
Clinical data
Other names	7α-TMS; SC-26519; 17α-Hydroxy-7α-(methylthio)-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
Drug class	Antimineralocorticoid
Identifiers
	IUPAC 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-dione;
CAS Number	38753-77-4;
PubChem CID	162325;
ChemSpider	142539;
UNII	0YU66JY4WL;
ChEMBL	ChEMBL3544705;
CompTox Dashboard (EPA)	DTXSID80959567 ;
Chemical and physical data
Formula	C23H32O3S
Molar mass	388.57 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES 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 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;

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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]

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Pharmacokinetics of 100 mg/day spironolactone and its metabolites
Compound	C_maxTooltip Peak concentrations (day 1)	C_maxTooltip Peak concentrations (day 15)	AUCTooltip Area-under-the-curve concentrations (day 15)	t_1/2Tooltip Elimination half-life
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-TMSTooltip 7α-Thiomethylspironolactone	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-TMSTooltip 6β-Hydroxy-7α-thiomethylspironolactone	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]

References

^ ^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, 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.
^ 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 7α-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 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.