Spironolactone structure

Spironolactone (Aldactone) is structurally related to aldosterone and acts as a competitive inhibitor to prevent the binding of aldosterone to its specific cellular binding protein. Spironolactone thus blocks the hormone-induced stimulation of protein synthesis necessary for Na+ reabsorption and K+ secretion. Spironolactone, in the presence of circulating aldosterone, promotes a modest increase in Na excretion associated with a decrease in elimination. 

Androstenolone, 1, can be transformed microbiologically to the 7a,15a-dihy-droxy derivative 2 by the action of Colletotrichium Uni. During formation of the acetal (3), inversion takes place on C-7. Acidic cleavage of 3 results in the triol, 4, which can also be produced by direct acidic catalysis from 2 [12,13]. After selective protection to the 3/l,15a-dipivalate (5), the 15/1,16/1-methylene compound, 6, can be synthetized, and then stereoselectively transformed to the 5/ ,6/ -epoxide, 7. This reacts with triphenylphosphine and tetrachloromethane in pyridine to produce the 7a-chloro derivative, 8. On treatment with zinc and acetic acid, 8 can be converted to the key compound 9, which has a 5/i-hydroxy-6-ene structure. Compound 9 can then be methylenated stereoselectively in the 6/1,7/1 position by the Simmons-Smith method. The last three steps - 10 —> 11 —> 12 — drospirenone -include the build-up of the spironolactone ring, after which water is lost from the molecule and oxidation affords drospirenone. 

In some cases, the simple modification of a drug structure can essentially modify the biological activity profile, whilst preserving some part of the original activity. Drospirenone (see Chapter 11-17), an orally active progestin contraceptive with antimineralcorticoid properties, is an example of an analogue-based drug discovery process that started from the diuretic spironolactone. 

Spironolactone (Aldactone) is structurally similar to aldosterone and competitively inhibits its action in the distal tubule (exchange of potassium for sodium) excessive secretion of aldosterone contributes to fluid retention in hepatic cirrhosis, nephrotic syndrome and congestive cardiac failure (see specific use in chapter 24), in which conditions as well as in primary h)q)ersecretion (Conn s syndrome) spironolactone is most useful. Spironolactone is also useful in the treatment of resistant hypertension, where increased aldosterone sensitivity is increasingly recognised as a contributory factor. 

In patients with hepatic cirrhosis, g)mecomastia was twice as common during treatment with spironolactone than with potassium camenoate (42 versus 20%) at equiactive doses (12). This difference may be related to structural characteristics unique to metabohtes of spironolactone, namely a thiol group at the 7-alpha position (SEDA-11, 200). 

Spironolactone, U5P. The structure of spironolactone. 7a-(acctyllhio)-17)S-hydroxy-3-oxopregn-4-ene-21 - carboxylic acid y-laclonc (Aldaclone). is shown in Figure 18-14. 

A newer drug, epierenone, has a structure similar to that of spironolactone and a similar mechanism of action. It was initially approved for use in the treatment of hypertension but it can now be used in the treatment of patients with left ventricular systolic dysfunction and congestive heart failure after myocardial infarction. It has a half-life of approximately 5 hours and undergoes hepatic metabolism to inactive metabolites as its main route of elimination. Clinical experience with epierenone is currently limited. 

A procedure for the determination of diuretics of different therapeutical character high (bumetanide, ethacrynic acid, furosemide), intermediate (bendroflumethiazide, chlorthalidone, hydrochlorothiazide, xipamide) and low (acetazolamide, amiloride, spironolactone, triamterene) efficacy diuretics, and the uricosuric agent probenecid, in urine samples, illustrates a method development implying the control of pH, surfactant and modifier [23]. The greatest analytical problems in the detection of these compounds are basically their wide variety of chemical structures, functional groups and protonation constants. This implies the use of several experimental conditions for their analysis with conventional aqueous-organic mobile phases and laborious liquid-liquid or solid-liquid extraction prior to chromatographic separation. In contrast, the same micellar eluent can produce a satisfactory separation after direct injection. 

Figure 2. Structure of the model drugs, (a) ketoprofen and (b) spironolactone.

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