Steroidal aldosterone antagonists

Liddle, G.W. (1957) Sodium diuresis induced by steroidal antagonists of aldosterone. Science, 126, 1016-1018. 

Spironolactone is the most clinically usehil steroidal aldosterone antagonist, and unlike GR antagonists, this compound is utilized much more frequendy than aldosterone agonists. Interfering with reabsorption and secretion in the late distal segment, this compound is predominantiy used with other diuretics. Canrenone, an olefinic metaboHte of spironolactone, and potassium canrenoate, in which the C-17 lactone has been hydrolyzed open, are also potent mineralocorticoid antagonists. 

It was known for some time that even after the corticoids had been separated from crude extracts of the adrenal cortex, the remaining material, the so-called "amorphous fraction" still possessed considerable mineralocorticoid activity. Aldosterone (250), one of the last steroids to be isolated from this fraction, proved to be the active principle. This compound proved to be an extremely potent agent for the retention of salt, and thus water, in body fluids. An antagonist would be expected to act as a diuretic in those edematous states caused by excess sodium retention. Although aldosterone has been prepared by both total and partial synthesis, the complexity of the molecule discouraged attempts to prepare antagonists based directly on the parent compound. 

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

Aldosterone (183) is one of the key steroid hormones involved in regulation of the body s mineral and fluid balance. Excess levels of this steroid quickly lead to marked retention of sodium chloride, water and, often as a consequence, hypertension. The aldosterone antagonist spironolactone (184) has proven of great clinical value in blocking the effects... 

Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. Onset and duration of its action are determined by the kinetics of the aldosterone response in the target tissue. Substantial inactivation of spironolactone occurs in the liver. Overall, spironolactone has a rather slow onset of action, requiring several days before full therapeutic effect is achieved. 

As a final example, hydroxylation of the A -steroids (83) and (84) can be accomplished microbially, and the products are useful in the synthesis of the aldosterone antagonist, spirorenone (85 Scheme 15)."Mi5... 

Spironolactone (see p. 534) is a competitive aldosterone antagonist which also blocks the mineralocorticoid effect of other steroids it is used in the treatment of primary hyperaldosteronism and as a diuretic, principally when severe oedema is due to secondary hyperaldosteronism, e.g. cirrhosis, congestive cardiac failure. 

Steroid hormone receptors (for gonadal steroids and adrenocortical steroids) are complex proteins inside the target cell. The steroid penetrates, is bound and translocates into the cell nucleus, which is the principal site of action and where RNA/protein synthesis occurs. Compounds that occupy the receptor without causing translocation into the nucleus or the replenishment of receptors act as antagonists, e.g. spironolactone to aldosterone, cyproterone to androgens, clomiphene to oestrogens. 

Mexitil mexiletine. mexrenoate potassium mexrenoic acid, mexrenoic acid (mexrenoate potassium [inn, usan]) is a steroid, an aldosterone-ANTAGONIST (potassium-sparing) DIURETIC, which can be used in antihypertensive therapy, mezacopride zacopride. 

Eplerenone, a selective MR modulator, was discovered decades ago and has recently received approval as a treatment for hypertension [77]. This synthetic steroid derivative has a higher specificity for MR relative to other nuclear receptors and works as a partial antagonist of aldosterone [78]. 

Laurent, H., Nickisch, K., Schillinger, E. et ol. (1986) Mespirenone and other 15, 16-methylene-17-spirolactones, a new type of steroidal aldosterone antagonists. Arzneimittelforschung, 36, 1583-1600. 

In the key step of a synthesis of spironolactone (an aldosterone antagonist, used as a diuretic) reductive carbonylation of the optically active steroidal alkynol ethisterone yields a saturated cyclic hemiacetal (lactol) 15 with rhodium(II) acetate dimer/triphenylphosphane in 90% yield173. This reaction proceeds without loss of optical information and is interpreted as a combination of hydroformylation and hydrogenation173. 

A small set of steroids prepared from androstanes feature a spirobutyrolactone at C17. These agents act as antagonists of aldosterone, the highly oxygenated steroid that controls serum electrolytes and blood volume. The antagonist action of the spirolactones is manifested as diuretic and antihypertensive activity. 

Aldosterone, essentially a corticosteroid in which the methyl group at Cjg is oxidized to a carboxaldehyde, was the last endogenous steroid to be isolated in a form suitable for structural studies. This hormone controls via its action on the kidney both body electrolyte balance and blood volume. A number of modified androstanes, all of which feamre a spirobutyrolactone at C17, act as aldosterone antagonists Those 17-spirobutyrolactones consequently show diuretic and... 

The aldosterone antagonist spironolactone (Figure 7.4), which is used as a diuretic and antihypertensiveinactivates P450 enzymes in both the liver and steroidogenic tissues ", including the adrenal steroid ITof-hydroxylase " and... 

---