A structure-activity relationship study of spirolactones. Contribution of the cyclopropane ring to antimineralocorticoid activity.

A series of spirolactones containing a cyclopropane ring in the molecule was examined for its effects on the mineralocorticoid receptor. The results were compared with those of a similar series of spirolactones in which the cyclopropane ring was replaced by a double bond. Insertion of a double bond or an alpha-cyclopropane ring into the 1,2 or the 6,7 position leads to a reduction in the binding affinity. The pi-bonding system of the beta-cyclopropane ring at C-6 and C-7 does not promote binding to the receptor. The presence of the 6 beta, 7 beta-cyclopropane ring may deter metabolic activation to account for the enhanced in vivo activity.

Hypolipidemic activity of 5-aryl-3-methylvaleric acid derivatives.

Several 5-aryl-3-methylvaleric acid derivatives have been shown to be more potent hypolipidemic agents than the previously reported 5-(4-biphenylyl)-3-methylvaleric acid (1). The most active compound in this series was 5-(4-phenylsulfonylphenyl)-3-methylvaleric acid (10) which lowered serum cholesterol levels 45% and serum triglyceride levels 60% in normal rats. Significant lowering of the serum triglyceride levels was the predominant effect noted with most of the compounds tested.

Ring D oxygenated Spirolactones. Characterization of human metabolic product of spironolactone.

15alpha-Hydroxycanrenone (1b) was prepared from canrenone (1a) by microbiological oxidation with a penicillium species. The product was identical with one obtained from the metabolism of spironolactone(3) in human. Oxidation of 1b with Jones regent furnished the corresponding 15-oxocanrenone (1d) which underwent base-catalyzed beta elimination to generate an alpha,beta-unsaturated cyclopentenone system. 15alpha-Hydroxycanrenone (1b) failed to show antimineralocorticoid activity at the screening dose of 2.4 mg while the oxo derivative 1d exhibited approximately 15% the activity of 3. Since the activity of canrenone is 38% that of spironolactone, introduction of the carbonyl group at the 15 position of canrenone resulted in a reduction in activity. This effect is opposite to that observed with 6-dehydroprogesterone.

Potential hypolipidemic agents derived from 3-hydroxy-17,17-dimethylgona-1,3,5(10),8,11,13-hexaene.

Numerous aryloxy derivatives containing a lipophilic group have been found to possess hypolipidemic activity. This has prompted the preparation of various derivatives of 3-hydroxy-17,17-dimethylgona-1,3,5(10),8,11,13-hexaene (6a). In 6a the lipophilic biphenyl group is incorporated into the steroid nucleus. A three-step synthesis of 6a from 17beta-methylestradiol methyl ether was developed. The derivatives prepared were tested in rats made hypercholesterolemic with propylthiouracil. Several were found active in this test.

Spironolactone metabolism in man studied by gas chromatography-mass spectrometry.

Gas chromatography-mass spectrometry was used to identify metabolites of spironolactone in human blood and urine. In three healthy men about 20% of the radioactivity was excreted in the urine within 24 hr after an oral dose of [20-3H]spironolactone (200 mg + 200 muCi). About half of this radioactivity was extracted with chloroform at pH 3 and from this extract four stable metabolites were isolated by use of column and thin-layer chromatography. Two of these were the previously identified metabolites, canrenone (VII; 2.9% of dose) and the 6beta-hydroxy-sulfoxide (X; 1.8% of the dose). The remaining were the new metabolites, 15alpha-hydroxycanrenone (XI; 0.8% of dose) and the 6beta-hydroxy-thiomethyl derivatives (VI; 0.5% of dose). The principal water-soluble urinary metabolite was canrenoate ester glucuronide (XII; 4.5% of dose). In the 24- to 32-hr pooled serum, canrenone (VII) was the principal metabolite in the organic-extractable fraction; VI was present in appreciable amounts but X and XI were present at extremely low levels.

Potassium prorenoate: a new steroidal aldosterone antagonist.

Potassium prorenoate (SC-23992) is a water-soluble steroidal compound with the ability to antagonize the sodium-retaining and, when apparent, the potassium-dissipating effects of mineralocorticoids. A significant natriuretic response was obtained at dosages of 1 mg/kg and approximately 1.8 mg/kg in the dog and rat, respectively. Based upon an elevation in the previously depressed urinary log Na/K ratio, prorenoate possesses an oral potency of 4.6 and 8.1 times that of spironolactone (S), respectively, in the aldosterone and deoxycorticosterone acetate-treated adrenalectomized rat. In the aldosterone-treated dog, the compound had 3.0 times the potency of S and 2.2 times that of a related steroid, potassium canrenoate (SC-14266). Prorenoate and S are relatively inactive at the renal level in adrenalectomized rats without mineralocorticoid replacement. Prorenoate possesses no more than 2% of the natriuretic activity of hydrochlorothiazide in the intact animal. Clearance studies in dogs indicate a direct renal tubular site of interaction between prorenoate and aldosterone independent of changes in renal hemodynamics. The natriuretic response occurred within 100 minutes after a single oral dose and was sustained for at least 7 hours. Prorenoate possesses the pharmacological characteristics of an aldosterone antagonist, in common with those of S.

Synthesis of 15-keto-6beta, 7beta-methyleneprogesterone. Effect of the 6beta, 7beta-methylene group on mineralocorticoid activity.

15-Ketoprogesterone is as active as spironolactone in blocking the mineralocorticoid effect of deoxycorticosterone acetate. This activity is reduced when a methylene group is attached to the 6beta, 7beta position. The title compound was prepared from 15alpha-acetoxy-6-dehydroprogesterone. Methylenation of the delta6 double bond with dimethyloxosulfonium methylide proceeds steroselectively from the beta side of the molecule.