RESUMO
Investigation of the chemistry of the potent new uricosuric diuretic indacrinone (MK-196) led to a class of novel annulated derivatives, indeno[5,4-b]furan-2-carboxylic acids. The structural requirements for optimal diuretic and uricosuric activity of the tricyclic analogues differed from those of their (indanyloxy)acetic acids counterparts. Most notably, the tricyclic analogues were two to four times more natriuretic than the corresponding (indanyloxy)acetic acids when administered orally to rats, and in chimpanzees, uricosuria was observed only in those indenofurans having a nuclear aryl substituent.
Assuntos
Diuréticos/síntese química , Indanos/síntese química , Indenos/síntese química , Uricosúricos/síntese química , Animais , Fenômenos Químicos , Química , Indanos/farmacologia , Pan troglodytes , Ratos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
A variety of [(2-substituted and 2,2-disubstituted vinyl)aryloxy]acetic acids was synthesized in which the substituents were primarily electron-withdrawing groups. These compounds were tested in dogs for their saluretic and diuretic properties. Many of the compounds exhibited significant activity; however, they were generally less potent than those reported in the three earlier papers in this series.
Assuntos
Acetatos/síntese química , Diuréticos/síntese química , Acetatos/administração & dosagem , Acetatos/farmacologia , Administração Oral , Animais , Cloretos/urina , Diurese/efeitos dos fármacos , Diuréticos/administração & dosagem , Cães , Feminino , Injeções Intravenosas , Potássio/urina , Sódio/urina , Relação Estrutura-Atividade , Compostos de Vinila/administração & dosagem , Compostos de Vinila/síntese química , Compostos de Vinila/farmacologiaRESUMO
The introduction of an aryl group at the 2 position of the uricosuric diuretics, (1-oxo-2-alkyl-5-indanyloxy)acetic acids, provided compounds with markedly increased potency over their monosubstituted precursors. These compounds were synthesized either by arylation of the corresponding 2-alkyl-5-methoxy-1-indanones with diaryliodonium salts or by alkylation of the 2-aryl-5-methoxy-1-indanones which were cleaved to the corresponding phenols and then converted to the desired oxyacetic acids. Systematic structural variation of the 2-arylindanyloxyacetic acids provided aryl-substituted compounds with varying degrees of uricosuric and diuretic activity.
Assuntos
Acetatos/síntese química , Diuréticos/síntese química , Acetatos/farmacologia , Animais , Cloretos/urina , Cães , Natriurese/efeitos dos fármacos , Pan troglodytes , Potássio/urina , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Uricosúricos/síntese químicaRESUMO
In search of a drug to treat sickle cell anemia, several analogues of the diuretic ethacrynic acid (ECA) have been synthesized and found equivalent in antigelling potency to ECA, but they have moderate or little diuretic activity. Structure-activity studies revealed that most of the highly active derivatives contain an acryloyl moiety. The latter functionality reacts covalently with protein sulfhydryl groups via a Michael addition reaction. Other derivatives, which lack the acryloyl moiety, showed notably lower antigelling activity. Since the antigelling assay is run under anaerobic conditions, activity implies a stereochemical inhibition of polymerization of deoxyhemoglobin S. The solubility ratios obtained from [HbS drug]/[HbS control] of several compounds (Table I) are near those expected for a drug with clinical potential (1.06-1.20 at tolerable doses in vivo).
Assuntos
Antidrepanocíticos/síntese química , Ácido Etacrínico/análogos & derivados , Animais , Fenômenos Químicos , Química , Diuréticos/síntese química , Diuréticos/farmacologia , Cães , Desenho de Fármacos , Ácido Etacrínico/síntese química , Ácido Etacrínico/farmacologia , Sódio/urina , Relação Estrutura-AtividadeRESUMO
The discovery of the (acryloylaryloxy)acetic acids as a new class of potent diuretics prompted the investigation of related bicyclic compounds. Annelated analogues of the parent series, the (2-alkyl- and 2,2-dialkyl-1-oxo-5-indanyloxy)acetic acids, were the subjects of this study. Those compounds, unlike the monocyclic parent compound, lacked the double bond adjacent to the carbonyl group. More importantly, they possessed both saluretic and uricosuric properties. The optimal single 2-substituents for maximal saluretic and uricosuric activity were determined. In general, better activity was observed when a second 2-alkyl substituent (especially methyl) was present in the molecule. Replacement of the carboxy substituent by 5-tetrazolyl generally resulted in a reduction in activity.
Assuntos
Acetatos/síntese química , Diuréticos/síntese química , Acetatos/administração & dosagem , Acetatos/farmacologia , Administração Oral , Animais , Diurese/efeitos dos fármacos , Diuréticos/administração & dosagem , Cães , Feminino , Indanos/administração & dosagem , Indanos/síntese química , Indanos/farmacologia , Injeções Intravenosas , Masculino , Natriurese/efeitos dos fármacos , Pan troglodytes , Ratos , Sódio/urina , Relação Estrutura-Atividade , Uricosúricos/administração & dosagem , Uricosúricos/síntese químicaRESUMO
Investigation of the chemistry of the potent uricosuric diuretic indacrinone (MK-196) prompted the synthesis of a series of 3-oxo derivatives, i.e., the indan-1,3-diones. In general, both pharmacological parameters (uricosuria and diuresis) were significantly less pronounced with the 1,3-diones than with the parent 1-oxo compounds.
Assuntos
Diuréticos/síntese química , Glicolatos/síntese química , Indanos/síntese química , Indenos/síntese química , Uricosúricos/síntese química , Administração Oral , Animais , Diuréticos/administração & dosagem , Cães , Furosemida/farmacologia , Glicolatos/administração & dosagem , Glicolatos/farmacologia , Indanos/administração & dosagem , Indanos/farmacologia , Injeções Intravenosas , Masculino , Pan troglodytes , Ratos , Relação Estrutura-Atividade , Uricosúricos/administração & dosagemRESUMO
The discovery that dihydroethacrynic acid and other (4-acylphenoxy)acetic acids possessed modest but significant uricosuric and diuretic activity prompted our investigation of the related 2,3-dihydro-5-acyl-2-bensofurancarboxylic acids. Synthetic routes to a number of these compounds are presented along with the structure-activity relationships generated from studies in rats, dogs, and chimpanzee. Examination of the enantiomers of 6,7-dichloro-2,3-dihydro-5-(2-thienylcarbonyl)-2-benzofurancarboxylic acid (10c) in the chimpanzee revealed that all diuretic and saluretic activity is due to the (+) enantiomer 10d, while the (-) enantiomer 10e is responsible for all of the uricosuric activity. X-ray analysis showed that the (-) enantiomer 10e possesses the 2R configuration.
Assuntos
Benzofuranos/síntese química , Diuréticos/síntese química , Uricosúricos/síntese química , Animais , Benzofuranos/farmacologia , Fenômenos Químicos , Química , Cães , Pan troglodytes , Ratos , Especificidade da Espécie , Relação Estrutura-Atividade , Difração de Raios XRESUMO
Our initial paper discussed brain edema resulting from traumatic head injury and the need for specific and effective agents to treat the disorder and disclosed a novel approach for the discovery of a drug of this kind. The current study describes the synthesis of a series of [(2,3,9,9a-tetrahydro-3-oxo-9a-substituted-1H-fluoren-7-yl)oxy]alk anoic acids and their analogues. These compounds were evaluated in an in vitro cerebrocortical tissue slice assay for their relative potencies in inhibiting K+ + HCO3- induced swelling. Structural modification at a number of sites in the "lead" compound revealed that significant biological activity was inherent only within a very narrow range of structural types. The observation that nearly all the biological activity resided in one of the two enantiomers demonstrated the marked stereospecificity of the most active compounds. One of the most potent compounds, (R)-(+)-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren -7-yl) oxy]acetic acid ((+)-5c), exhibited a dose-response relationship in the in vivo acceleration/deceleration brain edema assay, and the data from the two highest doses were statistically significant. Electron microscopic examination demonstrated that the perivascular astroglial swelling that arises from this procedure is abolished in the animals treated with (+)-5c. This compound is currently being evaluated for its clinical efficacy and safety in the treatment of traumatic head injury.
Assuntos
Edema Encefálico/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Gatos , Cloretos/metabolismo , Traumatismos Craniocerebrais/complicações , Relação Dose-Resposta a Droga , Cobaias , Neuroglia/ultraestrutura , Ratos , Relação Estrutura-Atividade , Difração de Raios XRESUMO
A series of O-acyl derivatives of 6-hydroxybenzothiazole-2-sulfonamide (4, L-643,799) was prepared and the potential utility of each series member as a topically active inhibitor of ocular carbonic anhydrase was determined. In vitro studies showed these esters to be substrates for ocular esterases which liberate 4 during corneal translocation. The most interesting series member, 2-sulfamoyl-6-benzothiazolyl 2,2-dimethylpropionate (22, L-645,151), acting as a prodrug form of 4, was found to enhance delivery through the isolated albino rabbit cornea by 40-fold when compared to the parent phenol 4. Studies in rabbits revealed that 22 is a potent topically active ocular hypotensive carbonic anhydrase inhibitor.
Assuntos
Inibidores da Anidrase Carbônica , Etoxzolamida/farmacologia , Tiazóis/farmacologia , Animais , Benzotiazóis , Inibidores da Anidrase Carbônica/síntese química , Fenômenos Químicos , Química , Córnea/enzimologia , Etoxzolamida/administração & dosagem , Etoxzolamida/síntese química , Cobaias , Humanos , Pressão Intraocular/efeitos dos fármacos , Soluções Oftálmicas , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Coelhos , Tiazóis/administração & dosagem , Tiazóis/síntese químicaRESUMO
Blunt and ischemic injuries of the brain have been shown to result in swelling that is predominantly limited to a single cell type, the astrocyte, within the complex cellular mosiac of cerebral gray matter. Evaluation of various diuretic (aryloxy)acetic acids in vitro using incubating cat brain slices and primary astrocyte cultures identified compounds with marked ability to inhibit brain tissue swelling. Some of the compounds significantly reduced the mortality and morbidity following acceleration/deceleration brain injury in anesthesized cats. A variety of (indanyloxy)alkanoic acids were synthesized which were analogous to the dually active (indanyloxy)acetic acids. Some of the 4-(indanyloxy)butanoic acids were found to be devoid of diuretic activity but to possess equal or greater activity than the dually active compounds in the in vitro and in vivo brain assays. Selected examples from both the (indanyloxy)acetic and 4-(indanyloxy)butanoic acid series showed marked chiral effects, with one enantiomer generally exhibiting a much greater activity than the other. A clinical study of severely head-injured patients treated with ethacrynic acid demonstrated a significantly improved outcome when compared to controls. These data suggest a clinical advantage for the nondiuretic (aryloxy)alkanoic acids which possess in vitro and in vivo activities in the cat brain assays that are comparable or superior to dually active compounds.
Assuntos
Lesões Encefálicas/tratamento farmacológico , Ácidos Carboxílicos/síntese química , Animais , Astrócitos/efeitos dos fármacos , Bicarbonatos/farmacologia , Ácidos Carboxílicos/farmacologia , Gatos , Córtex Cerebral/metabolismo , Fenômenos Químicos , Química , Eletroencefalografia , Ácido Etacrínico/farmacologia , Técnicas In Vitro , Indanos/síntese química , Indanos/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de TempoAssuntos
Diuréticos/síntese química , Guanidinas/síntese química , Pirazinas/síntese química , Animais , Clorotiazida/farmacologia , Desoxicorticosterona/antagonistas & inibidores , Diurese/efeitos dos fármacos , Diuréticos/farmacologia , Cães , Guanidinas/farmacologia , Hidroclorotiazida/farmacologia , Métodos , Natriurese/efeitos dos fármacos , Pirazinas/farmacologia , RatosAssuntos
Diuréticos/síntese química , Indanos/síntese química , Indenos/síntese química , Uricosúricos/síntese química , Acetatos/síntese química , Animais , Cloretos/urina , Diurese/efeitos dos fármacos , Diuréticos/farmacologia , Cães , Feminino , Glicolatos/síntese química , Glicolatos/farmacologia , Indanos/farmacologia , Masculino , Pan troglodytes , Potássio/urina , Ratos , Sódio/urina , Estereoisomerismo , Relação Estrutura-Atividade , Uricosúricos/farmacologiaRESUMO
The mechanism of uptake of a series of amiloride derivatives by human neutrophils was investigated using [14C]amiloride and the 14C-labeled 5-(1-hexahydroazepinyl)-6-bromo analogue (BrMM) which is approximately 500-fold more potent than the parent compound at inhibiting Na+/H+ exchange. At an external concentration of 2 microM, the influx of BrMM at 37 degrees C was rapid, reaching a steady state by approximately 20 min. The rate of BrMM uptake (approximately 25 mumol/liter.min) was approximately 90-fold faster than for the same concentration of amiloride, a finding which correlates with differences in lipid partitioning of the two compounds. Uptake was unrelated to specific binding to Na+/H+ exchange transport sites: influx of either drug was nonsaturable whereas amiloride- and BrMM-mediated inhibition of Na+/H+ countertransport obeyed Michaelis-Menten kinetics with apparent Ki values of approximately 75 and approximately 0.2 microM. Entry occurred exclusively via the neutral (uncharged) forms (pK'a 8.40-8.55). Influx was markedly pH-dependent: it was enhanced by extracellular alkalinization and reduced by acidification. Influx was, however, insensitive to large changes in membrane voltage, thereby implying the protonated (charged) species to be impermeant. About 75% of the total intracellular pool of amiloride, but only approximately 25% of BrMM, is contained within the lysosomes, an expected consequence of the partitioning and subsequent trapping of a weak base within this strongly acidic subcellular compartment. With BrMM, there was a relative approximately 60-fold enrichment in the internal/external water concentration ratio of the drug; the value for amiloride was much less, approximately 4. This disparity is consistent with substantial binding of BrMM to internal constituents, presumably to proteins and/or nucleic acids. Thus, it is important to recognize that potentially large intracellular accumulations of potent analogues can occur that are not directly involved in inhibition of Na+/H+ exchange. These findings sound a cautionary note in the interpretation of results using these drugs in all cells, especially those of small size with high surface-to-volume ratios.
Assuntos
Amilorida/análogos & derivados , Amilorida/sangue , Neutrófilos/metabolismo , Transporte Biológico , Radioisótopos de Carbono , Humanos , Técnicas In Vitro , Cinética , Relação Estrutura-AtividadeRESUMO
Cats, injured by a mechanical plus hypoxic model of traumatic brain injury, were treated by intracisternal injection of a modified loop diuretic (L-644,711). This drug inhibits the chloride/bicarbonate anion exchange transport system. The treatment resulted in a significant decrease in mortality from 61 to 21%, and an improvement in both neurological status and EEG activity of the surviving animals. The dose of drug given intracisternally was at least 175 times less than the dosage we previously found was needed to achieve a comparable effect when the drug was given intravenously. The present results suggest that certain types of head injury can be treated by drugs which affect cellular anion transport processes in the brain.