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Registration Number

0216U000527, 0113U001283 , R & D reports

Title

Search of biologically active substances that will be able to suppress the action of risk vascular factor, which are connected with type 2 diabetes mellitus, at the expense of modulating extra-adrenal metabolism of glucocorticoids

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Head

Poltorack Victoria Vitaliivna, Доктор медичних наук

Registration Date

08-02-2016

Organization

State Institution "V. Danilevsky Institute for Endocrine Pathology Problems National Academy of Medical Sciences of Ukraine"

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The objects of research:rats, mice, condensed and spiro - nitrogen - and sulfur-containing heterocyclic compounds.The purpose of this work is to identify among derivatives of nitrogen and sulfur-containing heterocycles of new compounds which able to inhibit the development of the determining pathogenetic links of type 2 diabetes mellitus (insulin resistance and associated metabolic abnormalities, apoptosis of pancreatic beta-cells), due to the influence on intracellular conversion of inactive glucocorticoids to active in target tissues. Methods of research: organic synthesis, physico-chemical analysis, biochemical, biophysical, pharmacological, molecular biological, and computational. The methods of new structural types of heterocyclic substances synthesis have been worked out; more than 160 previously undescribed sulphur and nitrogen containing compounds have been synthesised; computer-aided screening by molecular docking method on 3D-model of human (PDB ID 3BZU) and mice (PDB ID 1Y5M) 11beta-HSD1 using the AutoDock 4.2 program has been carried out; and the most promising targets for pharmacological tests have been selected. As a result of the comparison of the initial pharmacological screening data 12 the most promising compounds have been selected for further study. Complex anti-diabetic properties of the four synthesized promising 11beta-HSD1 inhibitors in experimental models of type 2 diabetes in rats have been evaluated. As a result of the assessment of acute toxicity of the compounds 2703, 2708 and Ser00211 there was established that they belong to low-toxic substances (grade 4 of toxicity). In experimental models of type 2 diabetes in rats under two-week oral dosage there were verified the hypoglycemic, insulinsensitizing, body weight, the of abdominal fat fraction mass and blood pressure normalizing effects of compounds 2418 and AD-1408, which were not inferior to comparison drug Metformin. For compound Ser00211 there were verified the pronounced hypoglycemic, hypolipidemic, insulinsensitizing, antioxidant and aimed at the survival of the liver and pancreas cells effects, which were not inferior to comparison drug Metformin. 15-day oral administration of the compound Ser00211 was resulted in decrease in body weight and abdominal fat weight and blood pressure improvement in rats with experimental type 2 diabetes and was more effective than reference drug. Field of application: healthcare, pharmaceutical industry.

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Бородіна В.
Бурма Т.
Вакула В.
Гавриш Т.
Гладких О.
Завадська Н.
Карножицька Т.
Кравченко С.
Красова Н.
Кудря М.
Ліпсон В.
Лещенко Ж.
Нікішина Л.
Овсяннікова Т.
Полторак В.
Світлична Н.
Селюкова Н.
Тижненко Т.
Устенко Н.
Яременко Ф.

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2020-04-02