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1.
J Med Chem ; 65(24): 16420-16431, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36475653

RESUMO

Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit. Key aspect of the optimization was a switch in metabolism of our lead structures from glucuronidation to oxidation. The switch proved being essential for the identification of compounds with improved pharmacokinetic profiles. By studying a tool compound in a transverse aortic constriction mouse model, we were able to substantiate the relevance of PDE9A inhibition in heart diseases.


Assuntos
GMP Cíclico , Insuficiência Cardíaca , Camundongos , Animais , GMP Cíclico/metabolismo , Ensaios de Triagem em Larga Escala , 3',5'-AMP Cíclico Fosfodiesterases
2.
Am J Physiol Renal Physiol ; 320(1): F61-F73, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33196323

RESUMO

Oxidative stress is a key concept in basic, translational, and clinical research to understand the pathophysiology of various disorders, including cardiovascular and renal diseases. Although attempts to directly reduce oxidative stress with redox-active substances have until now largely failed to prove clinical benefit, indirect approaches to combat oxidative stress enzymatically have gained further attention as potential therapeutic strategies. The pantetheinase Vanin-1 is expressed on kidney proximal tubular cells, and its reaction product cysteamine is described to negatively affect redox homeostasis by inhibiting the replenishment of cellular antioxidative glutathione stores. Vanin-1-deficient mice were shown to be protected against oxidative stress damage. The aim of this study was to elucidate whether pharmacological inhibition of Vanin-1 protects mice from oxidative stress-related acute or chronic kidney injury as well. By studying renal ischemia-reperfusion injury in Col4α3-/- (Alport syndrome) mice and in vitro hypoxia-reoxygenation in human proximal tubular cells we found that treatment with a selective and potent Vanin-1 inhibitor resulted in ample inhibition of enzymatic activity in vitro and in vivo. However, surrogate parameters of metabolic and redox homeostasis were only partially and insufficiently affected. Consequently, apoptosis and reactive oxygen species level in tubular cells as well as overall kidney function and fibrotic processes were not improved by Vanin-1 inhibition. We thus conclude that Vanin-1 functionality in the context of cardiovascular diseases needs further investigation and the biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven.


Assuntos
Injúria Renal Aguda/prevenção & controle , Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Nefrite Hereditária/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Amidoidrolases/genética , Amidoidrolases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Autoantígenos/genética , Autoantígenos/metabolismo , Linhagem Celular , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Fibrose , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Túbulos Renais Proximais/enzimologia , Túbulos Renais Proximais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrite Hereditária/enzimologia , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
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