RESUMO
Accumulation of intracellular sorbitol, the product of glucose reduction catalyzed by aldose reductase (AR) [EC 1.1.1.21], is thought to be the main culprit in the development of diabetic complications. A series of 3-arylalkyl-2,4,5-trioxoimidazolidine-1-acetic acids was prepared and tested for inhibitory activities towards AR and aldehyde reductase (ALR) [EC 1.1.1.2]. These derivatives showed strong inhibitory activity against AR without markedly inhibiting ALR. In particular, the compounds with 3-nitrophenyl, 4-chloro-3-nitrophenyl, and chloro-substituted benzothiazolyl groups as the aryl part showed powerful AR-inhibitory activity. The chloro-substituted benzothiazolyl compound showed an AR selectivity of more than 5,000 fold.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Hidantoínas , Imidazóis/química , Animais , Inibidores Enzimáticos/química , Rim/enzimologia , Cristalino/enzimologia , RatosRESUMO
Accumulation of intracellular sorbitol, the reduced product of glucose, catalyzed by aldose reductase (AR) (EC 1.1.1.21), is thought to be the cause of the development of diabetic complications. Our attention is focused on finding compounds which inhibit AR without significantly inhibiting aldehyde reductase (ALR) (EC 1.1.1.2). The uracil or 2,4-dioxoimidazolidine skeleton having the benzothiazolyl or 4-chloro-3-nitrophenyl group as an aryl part indicated not only extremely high AR inhibitory activity but also AR selectivity. The ratio of IC50(ALR)/IC50(AR) of 3-[(5-chlorobenzothiazol-2-yl)methyl]-1,2,3,4-tetrahydro-2,4- dioxopyrimidine-1-acetic acid (47d) was more than 17 500. The uracil skeleton with the benzothiazolyl moiety seemed to be the best combination for selective AR inhibition.
Assuntos
Acetatos/síntese química , Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Pirimidinonas/síntese química , Tiazóis/síntese química , Acetatos/química , Acetatos/farmacologia , Aldeído Redutase/metabolismo , Animais , Benzotiazóis , Complicações do Diabetes , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Rim/enzimologia , Cristalino/enzimologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Ftalazinas/química , Ftalazinas/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Ratos , Sorbitol/farmacologia , Sorbitol/toxicidade , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
A series of 3-(arylalkyl)-2,4,5-trioxoimidazolidine-1-acetic acids (1) was prepared and tested for aldose reductase (AR) and aldehyde reductase (ALR) inhibitory activities. These compounds showed strong inhibitory activity against AR without significant inhibitory activity for ALR. The ratio of IC50(ALR)/IC50(AR) was > 1000 in some compounds. On the basis of pharmacological tests such as the recovery of reduced motor nerve conduction velocity and toxicological profile, 3-(3-nitrobenzyl)-2,4,5-trioxoimidazolidine-1-acetic acid (NZ-314) was selected as the candidate for clinical development.
Assuntos
Acetatos/farmacologia , Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Acetatos/química , Animais , Inibidores Enzimáticos/química , Cobaias , Rim/enzimologia , Cristalino/enzimologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , RatosRESUMO
Methyl alpha- and beta-glycosides of N-acetylneuraminic acid (Neu5Ac) and N-acetyl-3 beta-hydroxyneuraminic acid (Neu5Ac beta 3OH) (1-4) were prepared to evaluate their calcium-binding ability. (Methyl alpha-glucopyranosidonyl) alpha- and beta-, and 4-methylumbelliferyl alpha-glycosides of Neu5Ac and Neu5Ac beta 3OH (5-10) were also synthesized for the comparison of chemical and enzymatic stabilities, respectively. Methyl beta-glycosides of Neu5Ac and Neu5Ac beta 3OH, 3 and 4, respectively, showed intense calcium-binding abilities, while no such ability was observed in the corresponding alpha-glycosides, 1 and 2. The Neu5Ac beta 3OH glycosides, 6, 8, and 10, showed much stronger resistance to acidic hydrolysis and sialidase digestion than the corresponding Neu5Ac glycosides, 5, 7, and 9.
Assuntos
Cálcio/química , Glicosídeos/química , Neuraminidase/química , Ácidos Siálicos/química , Animais , Bovinos , Estabilidade Enzimática , Hidrólise , Espectroscopia de Ressonância Magnética , Conformação Molecular , Ácido N-Acetilneuramínico , Relação Estrutura-AtividadeRESUMO
Stereospecificity of 3,4-dihydroxybutanoic acid gamma-lactone (3,4-DB) and 2,4,5-trihydroxypentanoic acid gamma-lactone (2,4,5-TP) in their effects on feeding behavior and humoral factors was assessed by infusion into the rat third cerebroventricle. Initial transient food intake was most potently affected by infusion of 2.50 mumol of the 2S,4S-stereoisomer of 2,4,5-TP (80%) at 1100 h. Among the others, 2.50 mumol of the 2R,4S-isomer was somewhat potent in feeding elicitation (20%). Feeding induced by these isomers was not accompanied by periprandial drinking. Ambulation increased with elicitation of feeding. During the first dark period after infusion at 1940 h, 2.50 mumol of the 3S-isomer of 3,4-DB decreased food intake, including reduced meal size, and prolonged postprandial intermeal interval, but the 3R-isomer did not. Potent hypoglycemia with hyperinsulinemia was caused by the 2S,4S-isomer of 2,4,5-TP, and the S-isomer of 3,4-DB caused responses that were reciprocal to those to 2,4,5-TP. The remaining isomers did not affect feeding or humoral factors. The results suggest that the S- or S,S-stereo-isomer of the endogenous organic acid gamma-lactones may be important in modulating food intake through the hypothalamus.