Application of valeramide compound as glutamate dehydrogenase inhibitor

Abstract

The invention provides an application of a valeramide compound (S)-N-(1H-indol-6-yl)-4-methyl-2-(1-oxoisoindol-2-yl) valeramide as a glutamate dehydrogenase (GDH) inhibitor, and particularly provides an application of the valeramide compound (S)-N-(1H-indol-6-yl)-4-methyl-2-(1-oxoisoindol-2-yl)-4-methyl-2-(1-oxoisoindol-2-yl) valeramide as a glutamate dehydrogenase inhibitor. The compound has an effective inhibition effect on the activity of glutamate dehydrogenase (GDH) under the condition of micromolar concentration, and can be used for preparing a medicine for preventing and treating diseases caused by the GDH. Glutamate dehydrogenase is a mitochondrial enzyme, and is a key enzyme for glutamic acid to enter tricarboxylic acid cycle to generate ATP (adenosine triphosphate). According to the present invention, the functional mutation of GDH is one of the reasons for the generation of the congenital hyperinsulinemia (CHI) in the newborn, and the generation of the functional mutation of GDH in the newborn is the one of the reasons for the generation of the congenital hyperinsulinemia (CHI) in the newborn; along with the development of research, more and more evidences show that GDH is closely related to activities such as proliferation, migration and invasion of tumor cells, and the phenomenon of abnormal expression exists in many tumor cells. The GDH inhibitor provided by the invention can well inhibit the activity of GDH, so that the effects of treating CHI caused by GDH mutation and finding effective cancer treatment drugs are achieved.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, in particular to a valeramide compound (S)-N-(1H-indol-6-yl)-4-methyl-2-(1-oxoisoindole-2 -yl) valeramide as an inhibitor of glutamate dehydrogenase. Background technique [0002] Congenital hyperinsulinism (CHI) is a persistent and intractable hypoglycemia caused by excessive insulin secretion and increased blood insulin concentration. The causes of hypoglycemia are complex (at least 11 causative genes have been found), and the main causative genes include: [0003] 1) Gain-of-function mutation of the key enzyme of amino acid metabolism, glutamate dehydrogenase (GDH); [0004] 2) Gain-of-function mutations in the key enzyme of glucose metabolism, glucokinase (GCK); [0005] 3) Loss-of-function mutations in ATP-dependent potassium channels (SUR1 and Kir6.2); [0006] 4) Loss-of-function mutations in key enzymes of fatty acid metabolism (SCHAD). [0007] Glutamate dehydrogenase (GDH) gain...

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Problems solved by technology

[0008] At present, the treatment methods and drugs for CHI are very limited. The first-line drug diazoxide is only suitable for one-third of neonatal hypoglycemia patients, and there is no treatment for brain dysfunction and liver and kidney damage, and it will cause water and sodium retention and Side effects such as hyperglycemia greatly limit the treatment of hypoglycemic children with these non-genetic diseases

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