RESUMO
A limited study was conducted to determine the biological consequences of rendering the phenyl rings of the previously reported 7-(3,5-disubstituted [1,1'-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids coplanar. Such constraint substantially diminished intrinsic HMG-CoA reductase inhibitory activity.
Assuntos
Caproatos/farmacologia , Fluorenos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases , Lactonas , Animais , Hidroxiácidos/farmacologia , Fígado/enzimologia , Ratos , Relação Estrutura-AtividadeRESUMO
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
A number of bicyclic ring-fused analogues of 2-(aminomethyl)phenol were synthesized and tested orally in rats and intravenously in dogs for saluretic and diuretic effects. Of the 15 alicylic, aromatic, and heterocyclic ring-fused compounds tested, only 2-(aminomethyl)-4-chloro-1-naphthalenol hydrochloride (2) and 7-(aminomethyl)-6-hydroxy-5,8-dimethyl-1,2,3,4-tetrahydronaphthalene hydrochloride (6) displayed a high order of activity.
Assuntos
Aminas/farmacologia , Benzilaminas/farmacologia , Diuréticos/síntese química , Animais , Benzilaminas/síntese química , Diurese/efeitos dos fármacos , Cães , Ratos , Cloreto de Sódio/urina , Relação Estrutura-AtividadeRESUMO
The synthesis of a number of 3,4-dihydrospiro-2H-1,3-benzoxazines and their corresponding benzoxazinium salts are reported. The saluretic effects displayed by these N,O-spiroannulated 2-(aminomethyl)phenols appear to be, in part, inversely related to their respective in vivo rates of hydrolysis. Good antihypertensive effects are found only in spirobenzoxazinium 22. Thus, a combination of spiroannulation and quaternization on 2 to produce 22 leads to a loss of saluretic effects with maintenance of antihypertensive effects and, thereby, serves to separate these pharmacological properties.
Assuntos
Aminas/farmacologia , Benzilaminas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Ratos , Cloreto de Sódio/urinaRESUMO
The synthesis and biological evaluation of 4-(aminomethyl)-6-(1,1-dimethylethyl)-2-iodo-3-pyridinol dihydrochloride (7b) are described. Compound 7b proved to be highly active as a saluretic diuretic in both rats and dogs.
Assuntos
Diuréticos/síntese química , Iodopiridonas/síntese química , Animais , Pressão Sanguínea/efeitos dos fármacos , Fenômenos Químicos , Química , Diuréticos/farmacologia , Cães , Eletrólitos/urina , Hipertensão/fisiopatologia , Iodopiridonas/farmacologia , RatosRESUMO
A series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives have been prepared and tested for inhibition of HMG-CoA reductase in vitro. In general, unless a carboxylate anion can be formed and the hydroxy groups remain unsubstituted in an erythro relationship, inhibitory activity is greatly reduced. Furthermore, only one enantiomer of the ring-opened form of lactone 6a(+/-) possesses the activity displayed by the racemate. Insertion of a bridging unit other than ethyl or (E)-ethenyl between the 5-carbinol moiety and an appropriate lipophilic moiety (e.g., 2,4-dichlorophenyl) attenuates activity.
Assuntos
Glicóis/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases , Lactonas/farmacologia , Ácidos Pentanoicos/farmacologia , Valeratos/farmacologia , Glicóis/síntese química , Lactonas/síntese química , Ácidos Pentanoicos/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The syntheses of a series of 7-(3,5-disubstituted [1,1'-bephenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactones are reported. Intrinsic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity is enhanced markedly when the biphenyl moiety is substituted by chloro or methyl groups at positions 3 and 5 and a fluoro group at position 4'. These substitutions, followed by resolution, provided compounds 100(+) and 110(+) with 2.8 times the intrinsic inhibitory activity of compactin. Compound 100(+) was shown to possess the same chirality in the lactone ring as compactin by single-crystal X-ray crystallography.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Animais , Lactonas/farmacologia , Ratos , 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 modified 2-(aminomethyl)phenols was synthesized and tested orally in rats for saluretic and diuretic effects. Intravenous dog data are included as supplementary material to show that the diuretic responses, or lack thereof, may be obtained in a second species. Reorientation of the 2-(aminomethyl) group either meta or para to the hydroxyl substituent resulted in loss of diuretic effects. Similarly, replacement of either the phenolic hydroxyl or the aminomethyl group with other functional moieties substantially diminished saluretic effects.
Assuntos
Aminas/síntese química , Benzilaminas/síntese química , Diuréticos/síntese química , Natriurese/efeitos dos fármacos , Animais , Benzilaminas/farmacologia , Fenômenos Químicos , Físico-Química , Conformação Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A series of oxygen and/or nitrogen substituted 2-(aminomethyl)phenols was synthesized and tested orally in rats for saluretic and diuretic effects. Intravenous dog data are included as supplementary material to demonstrate diuretic responses, or lack thereof, in a second species. In general, substitution on nitrogen with groups other than lower alkyl or substitution on nitrogen and/or oxygen with groups resistant to hydrolysis substantially diminished or ablated saluretic effects.
Assuntos
Natriurese/efeitos dos fármacos , Fenóis/síntese química , Animais , Fenômenos Químicos , Química , Cães , Hidrólise , Injeções Intravenosas , Nitrogênio , Oxigênio , Fenóis/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 2-(aminomethyl)phenols was synthesized and tested in rats and dogs for saluretic and diuretic activity. A number of these compounds exhibit a high order of activity on iv or po administration. The most active compounds belong to a subseries of 4-alkyl-6-halo derivatives of which 2, 2-(aminomethyl)-4-(1,1-dimethylethyl)-6-iodophenol, is the most active. Compound 2 also possesses significant antihypertensive activity, an adjunctive pharmacological parameter which distinguishes 2 from the other compounds prepared in this series. In addition, 2 displays both topical saluretic and antiinflammatory activities.
Assuntos
Diuréticos/síntese química , Natriurese/efeitos dos fármacos , Fenóis/síntese química , Administração Oral , Animais , Fenômenos Químicos , Química , Diuréticos/administração & dosagem , Cães , Feminino , Injeções Intravenosas , Fenóis/administração & dosagem , Fenóis/farmacologia , Ratos , Relação Estrutura-AtividadeAssuntos
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 structure-activity relationship of a series of non-thiol CaaX analogs, which are inhibitors of farnesyltransferase, is described. These inhibitors contain a substituted phenyl group at the N terminus, which may occupy a novel binding domain on the Ras protein.