We have previously shown that the isolated arginase 2 inhibitors have a pronounced endothelioprotective level. A strategy is proposed for the targeted search for isolated arginase 2 inhibitors among compounds of a phenolic nature. Received 3 compounds, isolated arginase inhibitors 2. As a result of the study, the acute toxicity of the compounds obtained was studie

Dolzhikov, A. A.

Galenko-Yaroshevsky, P. G.

Korokin, M. V.

Korokina, L. V.

Pokopejko, O. N.

Pokrovskaia, T. G.

Pokrovskii, M. V.

Reznichenko, L. V.

Yakovleva, E. G.

English

DSpace at Belgorod State University

Journal of International Pharmaceutical Research, ISSN: 1674-0440  Study of the Selective Phenolic Inhibitors of Arginase 2 Acute Toxicity  Liliya V. Korokina1*, Mikhail V. Pokrovskii2, Mikhail V. Korokin2, Olga N. Pokopejko2, Tatyana G. Pokrovskaia2,  Pavel G. Galenko-Yaroshevsky2, Alexandr A. Dolzhikov2, Lyudmila V. Reznichenko2 and Elena G. Yakovleva2  1. PhD in Medicine, Researcher of the Department of Pharmacology and Clinical Pharmacology, Medical Institute, Belgorod State National Research University, 85, Pobedy St., Belgorod, 308015, Russia.  2. Department of Pharmacology, Medical Institute, Belgorod State University, 85, Pobedy St., Belgorod, 308015, Russia. Correspondence author: Liliya V. Korokina, e-mail: korokina@bsu.edu.ru Received: 17-05-2019, Revised: 13-06-2019, Accepted: 15-07-2019, Published online: 23-08-2019 How to cite this article: Liliya V. Korokina, Mikhail V. Pokrovskii, Mikhail V. Korokin, Olga N. Pokopejko, Tatyana G. Pokrovskaia,  Pavel G. Galenko-Yaroshevsky, Alexandr A. Dolzhikov, Lyudmila V. Reznichenko and Elena G. Yakovleva (2019) Study of the Selective Phenolic Inhibitors of Arginase 2 Acute Toxicity, Journal of International Pharmaceutical Research 46(4): 258-261  Abstract Introduction: We have previously shown that the isolated arginase 2 inhibitors have a pronounced endothelioprotective level. A strategy is proposed for the targeted search for isolated arginase 2 inhibitors among compounds of a phenolic nature. Received 3 compounds, isolated arginase inhibitors 2. As a result of the study, the acute toxicity of the compounds obtained was studied. Objectives of the study: to substantiate the choice of a phenolic compound, a selective arginase 2 inhibitor, which has the lowest acute toxicity among the compounds obtained. Methods: The experiment was conducted on laboratory mice of both sexes. Substance administered intragastrically. Observation of the animals was carried out for 14 days. Results: Summarizing the data obtained, it can be concluded that, after intragastric administration to mice, the investigated compounds of phenolic nature under laboratory ciphers KUD259, KUD972, KUD973 are slightly toxic. Conclusion: As the main candidate for the drug, it is advisable to consider the compound KUD972, which showed the highest LD50 values, and therefore has the lowest toxicity. Keywords: Acute Toxicity, Arginase Inhibitors 2, Compounds of Phenolic Nature.  Introduction The basis of modern therapy of arterial hypertension and other cardiovascular diseases is the postulate of the need to correct endothelial dysfunction as an indicator of the adequacy of antihypertensive and other types of treatment. In fact, this means that lowering blood pressure (BP) without normalizing endothelial function cannot be considered a successfully solved clinical problem. "ADMA-eNOS" as a pharmacological target is of undoubted interest and has been the object of research by pharmacologists [1-6]. Studies have revealed the role of methylated derivatives of L-arginine monomethylarginine (L-NMMA) and asymmetric dimethylarginine (ADMA) as endogenous inhibitors of endothelial NO synthase (eNOS). Earlier studies have shown that preventing the accumulation and overcoming of inhibition of eNOS by an already established ADMA claims to be one of the ways to pharmacological correction endothelial dysfunction. Endothelium protective properties implemented by reducing the inhibitory effect of ADMA on eNOS agents such as L-arginine [7-8], tetrahydrobiopterin [9], non-selective arginase inhibitor L-norvaline [2, 5, 23], selective arginase II inhibitors [10-12, 25] and so forth, were experimentally confirmed. Thus, the urgent task of pharmacology is to search for substances that selectively affect the metabolism of nitric oxide, namely, selectively inhibit the enzyme Arginase 2. Currently, preclinical studies of toxicological safety, pharmacological activity, pharmacokinetics and bioequivalence are an integral part of the study of new drugs [13-22]. We have previously shown that selective arginase 2 inhibitors have a pronounced endothelioprotective effect [12, 24]. A strategy for targeted search for selective arginase 2 inhibitors among compounds of phenolic nature has been proposed. Using the methods of computer simulation and high-tech screening, we obtained 3 compounds, selective arginase inhibitor 2. Objectives of the study: to substantiate the choice of a phenolic compound, a selective arginase 2 inhibitor, which has the lowest acute toxicity among the compounds obtained. Materials and Methods Experiments on the study of acute toxicity were performed on laboratory mice of both sexes. The Journal of International Pharmaceutical Research, ISSN: 1674-0440 258   studied compounds of phenolic nature KUD259, KUD972, KUD973 were administered intragastrically once to the animals using metal probes with atraumatic smooth olives at the end in five doses. The individual volume of the injected dose for each animal was calculated based on the value of body weight. Phenolic compounds under laboratory ciphers KUD259, KUD972, KUD973 were administered intragastrically once in doses of 500, 600, 700, 800 and 900 mg / kg. In the study of "acute" toxicity, the clinical observation of each animal was carried out during the first hour after administration of the drug, daily for the next 14 days. The number of dead animals was counted during the experiment. Daily visually noted deviations in the consumption of food and water by animals in individual cells. At the opening of the dead animals visually inspected the internal organs, noted pathological changes in the color, size, location of organs. After completion of the experiment according to the method of B.M. Shtabsky counted LD50. Results Studies have shown that after intragastric administration to mice of the studied compounds of phenolic nature, in the indicated dosages, the death of animals was recorded. The death of animals occurred within 5-24 hours after priming. As a result of the study, the average lethal dose was calculated after intragastric administration of phenolic compounds to mice (Tables 1–4). After the introduction of the studied compounds, the intensity of physical activity decreased on average after 1-2 hours, coordination of movements was disturbed, the skeletal muscle tone decreased, the reaction to tactile, painful, sonic and light stimuli. After 2-24 hours, the frequency of respiratory movements increased, and the depth decreased with a subsequent decrease in the frequency of respiratory movements. The state of the hair and skin patches, did not change during the entire observation period. The amount and consistency of fecal masses, frequency of urination and urine color did not change in all experimental groups during the entire observation period. The surviving animals remained sluggish and sedentary for 1-2 days hours after acute seeding.    Table-1: Data characterizing the toxicity of compounds KUD259 phenolic nature in the study of "acute" toxicity in white mice after intragastric administration Group animal Dose, mg / kg Number of animals LD16 mg/kg LD50 mg/kg LD84 mg/kg Total Fallen Survivors    Control 0 10 0 10      KUD259 500 10 0 10 677.3 813.3 949.3 600 10 2 8 700 10 2 8 800 10 5 5 900 10 7 3  Table-2: Data characterizing the toxicity of compounds KUD972 of phenolic nature in the study of "acute" toxicity in white mice after intragastric administration Group animal Dose, mg / kg Number of animals LD16 mg/kg LD50 mg/kg LD84 mg/kg Total Fallen Survivors    Control 0 10 0 10      KUD972 500 10 0 10 723.3 808.3 893.3 600 10 0 10 700 10 3 7 800 10 4 6 900 10 7 3 Journal of International Pharmaceutical Research, ISSN: 1674-0440 259   Table-3: Data characterizing the toxicity of compounds KUD973 phenolic nature in the study of "acute" toxicity in white mice after intragastric administration Group animal Dose, mg / kg Number of animals LD16 mg/kg LD50 mg/kg LD84 mg/kg Total Fallen Survivors    Control 0 10 0 10      KUD973 500 10 1 9 556.2 604.8 653.3 600 10 5 5 700 10 8 2 800 10 10 0 900 10 10 0  Upon the death of animals after the administration of the compounds under study, animals were dissected in all experimental groups for macroscopic assessment of the state of the internal organs. Visual examination of the thoracic and abdominal cavities of the dead animals of all groups of macroscopically distinguishable changes was not detected. There were no pathological contents in the thoracic and abdominal cavities. According to the results of the autopsy and macroscopic examination of the internal organs of the dead experimental animals that received the test compounds, no pathological changes were found: TONGUE. The tongue is clear. ESOPHAGUS. The mucosa of the esophagus gray, smooth, shiny. STOMACH. Stomach with well pronounced folds of the mucous. Gray mucus-wet, shiny. LIVER. The liver is dense with a smooth surface, on a section of red-brown color. THICK AND SLIM INTESTINE. The contents of the intestine corresponds to each of its sections. Its mucosa forms transverse folds, moist, gray. LYZY LITTLES, TRAHEAS, MAIN BRONCHES pink, smooth, moist, shiny. A HEART. The heart is rounded, well cut. Under the epicardium, the usual venous pattern of the location of the coronary vessels. The flaps are thin, translucent. The endocardium is smooth and shiny. The aorta is elastic, its intima is clean, smooth. KIDNEYS. The capsule of the kidneys is easily removed, under it the smooth surface of the kidneys, on the incision of the kidney of moderate blood supply with a clear division into layers. Mucous pelvis, bladder gray, moist, shiny. SPLEEN. The spleen with a smooth capsule, in the cut gray-red, pulp scraping does not. BRAIN. The brain shells are translucent, smooth, shiny. Brains of the brain are well defined. On a section the substance of the brain is wet, brilliant, with a symmetrical pattern of the structure. The vessels of the base of the brain are arranged symmetrically, with collapsed walls. The organs of the thoracic and abdominal cavities are located correctly. Cavities are free from liquids and adhesions. LUNGS. Light air, gray-pink color, covered with a thin pleura, lower lobes with uneven blood filling. ADRENAL. The adrenal glands are round, with a clear division of the parenchyma into the cortical and cerebral zones. Conclusion Summarizing the data obtained, it can be concluded that, when administered intracellularly to mice, the test compounds of phenolic nature under laboratory ciphers KUD259, KUD972 and KUD973 are slightly toxic and belong to class IV toxicity. The most toxic compound with the lowest mean lethal dose is a phenolic compound under the laboratory cipher KUD973 (LD50 - 604.8 mg / kg). The least toxic compound with the highest average lethal dose is a phenolic compound under the laboratory coding KUD972 (LD50 - 808.3 mg / kg). Thus, as the main candidate for the drug, it is advisable to consider the compound KUD972, which showed the highest values of LD50, and therefore has the lowest toxicity. References 1. Korokin, M. V., Pokrovsky, M. V., Novikov, O. O., Gureev, V. 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Study of the selective phenolic inhibitors of arginase 2 acute toxicity

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Study of the selective phenolic inhibitors of arginase 2 acute toxicity

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