RESUMO
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.
Assuntos
Desoxicorticosterona/antagonistas & inibidores , Progesterona/análogos & derivados , Animais , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Cetosteroides/síntese química , Cetosteroides/farmacologia , Espectroscopia de Ressonância Magnética , Conformação Molecular , Rotação Ocular , Progesterona/síntese química , Progesterona/farmacologia , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Gonanos/síntese química , Hipolipemiantes/síntese química , Animais , Colesterol/sangue , Clofibrato/farmacologia , Feminino , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/fisiopatologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Propiltiouracila , Ratos , Triglicerídeos/sangue , Útero/anatomia & histologia , Útero/efeitos dos fármacosRESUMO
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.
Assuntos
Mineralocorticoides/antagonistas & inibidores , Espironolactona/análogos & derivados , Fenômenos Químicos , Química , Antagonistas de Receptores de Mineralocorticoides , Conformação Molecular , Receptores de Mineralocorticoides , Receptores de Esteroides/metabolismo , Espironolactona/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Canrenona/metabolismo , Pregnadienos/metabolismo , Espironolactona/metabolismo , Animais , Canrenona/análogos & derivados , Canrenona/farmacologia , Fenômenos Químicos , Química , Desoxicorticosterona/antagonistas & inibidores , Humanos , Penicillium/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Hipolipemiantes/síntese química , Valeratos/síntese química , Animais , Colesterol/sangue , Técnicas In Vitro , Lipídeos/biossíntese , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Relação Estrutura-Atividade , Triglicerídeos/sangue , Valeratos/farmacologiaAssuntos
Androstanos/síntese química , Mineralocorticoides/antagonistas & inibidores , Adrenalectomia , Androstenos/síntese química , Androstenos/farmacologia , Animais , Desoxicorticosterona/antagonistas & inibidores , Diurese/efeitos dos fármacos , Cetosteroides/síntese química , Cetosteroides/farmacologia , Lactonas/síntese química , Lactonas/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Antagonistas de Receptores de Mineralocorticoides , Potássio/urina , Ratos , Sódio/urina , Espironolactona/farmacologiaAssuntos
Anti-Inflamatórios/síntese química , Anticoncepcionais/síntese química , Antagonistas de Estrogênios , Secoesteroides/síntese química , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Carragenina , Colesterol/sangue , Anticoncepcionais/farmacologia , Edema/tratamento farmacológico , Estranos/síntese química , Estranos/farmacologia , Estranos/uso terapêutico , Feminino , Fertilidade/efeitos dos fármacos , Adjuvante de Freund , Masculino , Camundongos , Tamanho do Órgão , Gravidez , Coelhos , Ratos , Secoesteroides/farmacologia , Secoesteroides/uso terapêutico , Relação Estrutura-Atividade , Útero/efeitos dos fármacosRESUMO
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.
Assuntos
Espironolactona/metabolismo , Canrenona/análise , Cromatografia Gasosa , Cromatografia em Camada Fina , Humanos , Masculino , Espectrometria de Massas , Espectrofotometria Infravermelho , Espironolactona/sangue , Espironolactona/urina , Compostos de Sulfidrila/análise , Sulfóxidos/análiseRESUMO
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.