RESUMO
Efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid aldose reductase inhibitors. The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50>100 microM), a related enzyme involved in the detoxification of reactive aldehydes.
Assuntos
Acetatos/síntese química , Acetatos/farmacologia , Aldeído Redutase/antagonistas & inibidores , Benzotiazóis/síntese química , Inibidores Enzimáticos/síntese química , Acetatos/química , Aldeído Redutase/metabolismo , Benzotiazóis/química , Benzotiazóis/farmacologia , Domínio Catalítico , Doença Crônica , Simulação por Computador , Cristalografia por Raios X , Complicações do Diabetes/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50RESUMO
Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when dosed with [(14)C]lidorestat at 10 mg/kg po).
Assuntos
Aldeído Redutase/antagonistas & inibidores , Complicações do Diabetes/tratamento farmacológico , Ácidos Indolacéticos/síntese química , Tiazóis/síntese química , Aldeído Redutase/química , Aldeído Redutase/genética , Animais , Catarata/tratamento farmacológico , Doença Crônica , Cristalografia por Raios X , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Humanos , Ácidos Indolacéticos/farmacocinética , Ácidos Indolacéticos/farmacologia , Cristalino/metabolismo , Masculino , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Distribuição TecidualRESUMO
Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective (2-arylcarbamoyl-phenoxy)-acetic acid aldose reductase inhibitors. The compound class features a core template that utilizes an intramolecular hydrogen bond to position the key structural elements of the pharmacophore in a conformation, which promotes a high binding affinity. The lead candidate, example 40, 5-fluoro-2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-phenoxyacetic acid, inhibits aldose reductase with an IC(50) of 30 nM, while being 1100 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. In addition, example 40 lowers nerve sorbitol levels with an ED(50) of 31 mg/kg/d po in the 4-day STZ-induced diabetic rat model.