RESUMO
A series of phenylglyoxylic acids is described, many of which are able to promote carbohydrate oxidation in muscle tissue, thereby favorably altering the carbohydrate/fatty acid balance in situations where fatty acid utilization is elevated. Such situations are reported to occur in ischemic heart disease, particularly following myocardial infection. In an attempt to effectively deliver the phenylglyoxylic acids to the site of action within the cell, the L-(+)-phenylglycines were employed as prodrugs. These are known to be transaminated to phenylglyoxylic acids. L-(+)-2-(4-Hydroxyphenyl)glycine (25, oxfenicine) has been selected for clinical evaluation.
Assuntos
Metabolismo dos Carboidratos , Glioxilatos/farmacologia , Miocárdio/metabolismo , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Animais , Glioxilatos/metabolismo , Coração/efeitos dos fármacos , Masculino , Ácidos Mandélicos , Oxirredução , Complexo Piruvato Desidrogenase/análise , Piruvatos/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 5-(arylthio)-, 5-(arylsulfinyl)-, and 5-(arylsulfonyl)thiophene-2-sulfonamides is described and anticonvulsant activities are listed for the compounds. In most cases, the sulfones had the highest activity and the sulfides the least. Sulfones with 3- or 4-halo substituents generally had the highest activity, and one analogue, 5-[(4-fluorophenyl)sulfonyl]thiophene-2-sulfonamide (51, UK-17022), had an anticonvulsant ED50 fo 2 mg/kg when administered orally to mice. Compound 51 selectively increased cerebral blood flow in animals without an unacceptable level of diuresis.
Assuntos
Anticonvulsivantes , Inibidores da Anidrase Carbônica , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/enzimologia , Anidrases Carbônicas/metabolismo , Eritrócitos/enzimologia , Masculino , Camundongos , Fluxo Sanguíneo Regional , Relação Estrutura-AtividadeRESUMO
A series of imidazo[2,1-b]thiadiazole and imidazo[2,1-b]thiazolesulfonamide carbonic anhydrase inhibitors is described and their anticonvulsant activities are listed. Many of the compounds have the same degree of ionization as acetazolamide and methazolamide, but their higher lipophilicity means that they are more able to penetrate into the central nervous system. One compound, 6-tert-butyl-2-sulfamoylimidazo[2,1-b]-1,3,4-thiadiazole (8, UK-15,454) had an anticonvulsant ED50 of 2.6 mg/kg when administered orally to mice. 8 selectively increased cerebral blood flow in animals without producing a high level of metabolic acidosis.
Assuntos
Inibidores da Anidrase Carbônica/síntese química , Circulação Cerebrovascular/efeitos dos fármacos , Tiadiazóis/síntese química , Tiazóis/síntese química , Animais , Anticonvulsivantes/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Diuréticos/síntese química , Cães , Técnicas In Vitro , Masculino , Camundongos , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Tiadiazóis/farmacologia , Tiazóis/farmacologiaRESUMO
A search for potent inhibitors of EC 3.4.24.11, an enzyme which is found most abundantly in the kidney and which degrades atrial natriuretic factor, has led to the identification of UK-69,578. Structure-activity studies starting from substituted N-carboxymethyl dipeptide inhibitors resulted in the introduction of a cyclo-alkane P1' residue and in the replacement of the aza-link between P1 and P1' residues by a methylene group, with a net ten-fold potency gain. UK-69,578 increases endogenous ANF levels and produces natriuretic and diuretic responses intravenously in mice.