Study of Endothelial Protective Activity of Phenol-Derived Thrombin and Arginase-2 Inhibitors KUD-259 and KUD-974

Pokrovsky, M. V.; Корокин, М. В.; Kudryavtsev, Konstantin V.; Pokrovskaya, T. G.; Гудырев, О. С.; Гуреев, В. В.; Корокина, Л. В.; Поветкин, С. В.

doi:10.1007/s10517-017-3822-y

Cited by 3 publications

(5 citation statements)

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“…Previously, we developed and studied acute toxic effects [28,29] and the pharmacological activity of a number of phenolic compounds that are inhibitors of arginase-2 and thrombin. The pharmacological activity of the developed compounds is shown in our laboratory on various experimental models of endothelial dysfunction [30,31]. The leader -methyl ether (2 -((1hydroxy-naphthalen-2-yl) thio) acetyl) -D-proline compound was selected under the laboratory code KUD-975.…”

Section: Results and Dissectionmentioning

confidence: 99%

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et al. 2021

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A big risk factor for sensitization and allergic diseases is susceptibility to animal allergens. The most significant animal allergens are derived from mammals, besides mites and cockroaches. The experiments on the allergenic properties of KUD975 were carried out on bisexual sexually mature albino guinea pigs weighing 300 ± 20 g. During the initial assessment of allergenic and mutagenic properties, the allergenic properties of KUD975 were studied by setting up an active skin anaphylaxis reaction. Mutagenicity in the test of induction of dominant lethal mutations was studied. For research, outbred male rats weighing 180-220 g KUD975 was administered intragastrically at a dose of 106 mg/kg, which corresponds to a 40-fold estimated therapeutic dose. Planting intact females at the rate of 3 heads for each male was performed weekly according to the stages of spermatogenesis. The study of the allergenic effect in the formulation of the reaction of active skin anaphylaxis in guinea pigs and mutagenicity in the test for the induction of dominant lethal mutations of the phenolic compound methyl ester (2 -((1hydroxy naphthalene-2-yl) thio) acetyl) -D-proline under the laboratory code KUD975 showed no signs of allergenicity and mutagenicity of compound KUD975. Given the results of this study, as well as the previously conducted study of toxicological safety, pharmacological activity, methyl ester (2 -((1hydroxy naphthalene-2-yl) thio) acetyl) -D-proline KUD-975 can be recommended for further study as a medicinal agent acting on arignase-2 for the treatment and prevention of a number of endothelium-associated diseases.

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Section: Results and Dissectionmentioning

confidence: 99%

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“…The preclinical studies of the selective arginase II inhibitor ZB49-0010 in various pathology models showed its pronounced endothelial protective properties that are superior to those for the non-selective inhibitor of L-norvaline Nguyen et al 2016;Severinova et al 2019). The literature contains data on the endothelial protective properties of arginase II selective inhibitors KUD-259 and KUD-974 on the functional state of vascular endothelium (Pokrovskii et al 2017); however, to date, studies of their effectiveness have not been conducted in experimental preeclampsia yet. Thus, it becomes obvious that short-lived erythropoietin derivatives that do not have an erythropoietic effect and selective arginase II inhibitors can serve as another promising area for searching for new drugs to prevent and correct preeclampsia.…”

Section: Resultsmentioning

confidence: 99%

“…Another promising group of drugs for the treatment of hypertensive conditions in pregnant women is arginase inhibitors (Nguyen et al 2016;Severinova et al 2019). At the same time, arginase II inhibitors as being more selective are of particular interest (Pokrovskii et al 2017;Gureev et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…So, despite a wide range of drugs, objective reality dictates the need to search for and study the effectiveness of new and currently existing drugs aimed at the prevention and treatment of preeclampsia and its complications. There is evidence of endothelial protective properties of selective arginase II inhibitors KUD-259 and KUD-974 (Pokrovskii et al 2017); however, no studies of their effectiveness in experimental preeclampsia have been conducted yet.…”

Section: Introductionmentioning

confidence: 99%

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Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia

Локтева¹,

Rozhkov²,

Гуреев³

et al. 2020

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Citation: Lokteva TI, Rozhkov IS, Gureev VV, Gureeva AV , Zatolokina MA, Avdeyeva EV, Zhilinkova LA, Prohoda EE, Yarceva EO (2020) Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia. Research Results in Pharmacology 6(1): 29-40. https:// Abstract Introduction: Preeclampsia remains one of the most common causes of maternal and perinatal mortality worldwide. A significant role in the pathogenesis of this pathology is assigned to placental ischemia and endothelial dysfunction. Therefore, the aim of the present study was to study the effectiveness of asialized erythropoietin and arginase II selective inhibitors: KUD-259 and KUD-974 in the correction of morphofunctional disorders of the cardiovascular system in experimental preeclampsia. Materials and methods:The study was performed in 260 female Wistar rats, each weighing 250-300 g. An AD-MA-like preeclampsia was reproduced in the experiment. To assess the emerging morphofunctional disorders, the following parameters were used: blood pressure, coefficient of endothelial dysfunction, microcirculation in the placenta, proteinuria, fluid content in the omentum, concentration of terminal metabolites in the blood plasma, and morphometric parameters of fetuses. Results and discussion:The administration of arginase II selective inhibitor KUD-974 in combination with asialized erythropoietin leads to a pronounced correction of emerging changes: a decrease in systolic and diastolic blood pressure in 1.5 and 1.7 times, a decrease in proteinuria in 3.6 times and a decrease in fluid content in the omentum. When arginase II selective inhibitor KUD 974 and asialized erythropoietin are used with methyldopa, the positive effects of the former are enhanced. Conclusion:Arginase II selective inhibitors KUD-259 and KUD-974 and asialized erythropoietin have a pronounced positive effect on the correction of morphofunctional disorders in animals with ADMA-like preeclampsia.

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“…Now numerous promising molecules of drugs are being studied with a high potency to have cardioprotective, antiischemic and antiarrhythmic properties, to correct endothelial dysfunction in order to normalize regulation of vascular pressure and microcirculatory blood flow (Blinova et al 2016, Vasilkina et al 2016, Shakhno et al 2018, Pokrovskii et al 2017. Among the substances of the kinds, our attention was drawn to salts of 2-aminoethanesulfonic acid containing magnesium and dimethylphenylacetamide as a base.…”

Section: Introductionmentioning

confidence: 99%

2-aminoaethanesulfonic acid compounds possess protective property in reperfusion-induced heart jnjury

Kurganov¹,

Blinova²,

Семелева³

et al. 2018

RRP

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The study aim was to explore pharmacological effects of 2-aminoaethansulfonic acid compounds in reperfusion-induced heart injury. Materials and methods.The study was performed on rats and dogs of both sexes, isolated rats' hearts. Two compounds of 2-aminoethanesulfonic acid, magnesium-containing (LBK-527) and phenylacetamide-containing (LKhT-317) were investigated. Antiarrhythmic effects of the compounds were studied in coronary artery reperfusion 7, 30 and 120 min after acute myocardial ischemia modeling. The ability of the substances to limit the volume of reperfusion injury was investigated by differential indicator method. The influence of substances on the intensity of free radical processes in the myocardium, as well as the metabolic profile of coronary venous blood during reperfusion, was studied. Hemodynamic effects of the substances were studied during in vivo experiments, as well as on an isolated heart.Results and discussion. The compounds effectively prevent cardiac arrhythmias generation caused by myocardial reperfusion after 7, 30 and 120 minutes of ischemia. Prophylactic intravenous administration of LHT-317 and LBK-527 at higher therapeutic doses limit the size of rats' heart necrosis zone after occlusion-reperfusion syndrome develops, prevent reperfusion-induced excessive activation of free-radical processes in rat myocardium, activate the antiradical activity of the heart tissues, and optimize [O 2 ] and [CO 2 ] in coronary venous sinus blood of dogs. Cardioprotective effect of the compounds manifests in preserving myocardium contractile function, maintaing BP and stabilizing heart chronotropic function.Conclusions. The study analysis shows that 2-aminoethanesulfonic acid compounds have cardioprotective effect in reperfusion syndrome. Keywordsischemic and reperfusion heart injury, 2-aminoaethanesulfonic acid compounds, arrhythmia, hemodynamics, lipid oxidation, metabolic profile, isolated heart.

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Study of Endothelial Protective Activity of Phenol-Derived Thrombin and Arginase-2 Inhibitors KUD-259 and KUD-974

Abstract: We performed correction of endothelial dysfunction with phenol derivatives KUD-259 and KUD-974 containing heteroatomic and heterocyclic structures. Pharmacological activity of KUD-259 and KUD-974 surpassed that of L-norvaline, a non-selective arginase inhibitor.

Cited by 3 publications

References 4 publications

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Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia

2-aminoaethanesulfonic acid compounds possess protective property in reperfusion-induced heart jnjury

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