RESUMO
Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in patients with nonalcoholic steatohepatitis (NASH). The transcription factor Nrf2 (nuclear factor-erythroid-2-related factor 2) plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. As the cytosolic repressor kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2, activation of Nrf2 facilitated by its release from Keap1 may represent a promising strategy in the treatment of NASH. To test this hypothesis, we used two chemically distinct types of Nrf2 activator. One is the thiol-reactive agent oltipraz (OPZ), a typical Nrf2 activator, and the other is a novel biaryl urea compound, termed NK-252 (1-(5-(furan-2-yl)-1,3,4-oxadiazol-2-yl)-3-(pyridin-2-ylmethyl)urea). NK-252 exhibits a greater Nrf2-activating potential than OPZ. Furthermore, in vitro binding studies revealed that NK-252 interacts with the domain containing the Nrf2-binding site of Keap1, whereas OPZ does not. This finding indicates that NK-252 is more potent than OPZ due to its unique mechanism of action. For in vivo animal model studies, we used rats on a choline-deficient L-amino acid-defined (CDAA) diet, which demonstrate pathologic findings similar to those seen in human NASH. The administration of OPZ or NK-252 significantly attenuated the progression of histologic abnormalities in rats on a CDAA diet, especially hepatic fibrosis. In conclusion, by using Nrf2 activators with independent mechanisms of action, we show that, in a rat model of NASH, the activation of Nrf2 is responsible for the antifibrotic effects of these drugs. This strategy of Nrf2 activation presents new opportunities for treatment of NASH patients with hepatic fibrosis.
Assuntos
Fígado Gorduroso/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Aminoácidos/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Linhagem Celular , Colina/metabolismo , Dieta , Di-Hidropiridinas/farmacologia , Dioxinas/farmacologia , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fibrose , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Humanos , Peróxido de Hidrogênio/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch , Fígado/metabolismo , Masculino , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Ratos , Transaminases/sangue , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
A series of novel 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27, which furthermore showed the potent efficacy in in vivo studies.