The thesis of Sevryukov O. V. has given the theoretical generalization and the new solution of the actual scientific problem of pharmacology, aimed at increasing the effec-tiveness of pharmacocorrection of hypoxic states by using the compound of 1-phenethyl-5,7-dihydro-1H-pyrrolo[2,3-d]pyrimidine-2,4,6-trion) (dezapur) as an antihypoxant with antioxidant and antiexudative properties and a favourable safety profile.
For the first time, the paper studies 15 new compounds - derivatives of 5,7-dihydro-1H-pyrrolo[2,3-d]pyrimidine, synthesized at the Department of Organic Chemistry of the National pharmaceutical university by Associate Professor K. M. Sytnyk.
In the model of hemic hypoxia, in all 15 compounds tested, antihypoxic activity has been established. The antihypoxic activity of eight compounds KMS-162; -163; -172; -178; -179; -211; -214; -217 in a dose of 1/10 LD50 amounted to 89; 100; 103; 83; 94; 131; 94; 71% correspondingly, and was significantly higher than that of a mexidol (100 mg/kg). Six compounds of KMS-162; -176; -191; -211; -214; -217 have been detected in the model of acute tetrachlormethane hepatitis, as evidenced by a decrease of the TBA-active prod-ucts and increased level of reduced glutathione. In the carrageenan edema model, six com-pounds of KMS-178; -179; -217; -214; -191; -211 have shown antiexudative activity. The antiexudative activity of compounds KMS-191 and KMS-211 in a dose 10 mg/kg was no worse than the one of comparative drug voltaren in the dose 8 mg/kg.
The analysis of the "structure-activity" dependence has shown that the antihypoxic and antioxidant activity of the investigated compounds is due to the basic structure of
5,7-dihydro-1H-pyrrolo[2,3-d]pyrimidine. The absence of the biphenyl radical in the 5.5 position of the pyrrolo-pyrimidine cycle causes increase in these types of activity. The an-ti-exudative activity does not depend on the presence of the two phenolic radicals in the 5 position of the pyrrolo-pyrimidine system, and in the subgroup of compounds at these rad-icals has a certain pattern: it increases at extension of the aliphatic chain in the first posi-tion of the dezapurine system from three to five carbon atoms.
For further study based on the results of screening studies, compound KMS-211-1-phenethyl-5,7-dihydro-1H-pyrrolo[2,3-d]pyrimidine-2,4,6-trion (the conventional name "Desapur") has been chosen. In the model of hemic hypoxia, a median effective dose of dezapur has been determined at an intragastric administration of 10 mg/kg. It has been es-tablished that LD50 of dezapur at intragastric administration to mice and rats is over 5000 mg/kg. The LD50for intragastric administration to rats is 4250 mg/kg, to mice - 2916 mg/ kg. According to the classification of K. K. Sidorov, dezapur can be attributed to the V class toxicity - almost non-toxic substances. The chronic experiment has shown no toxic effect of dezapur on trophic processes, functional state of the CNS, cardiovascular system, liver, kidney, the cellular composition of blood, the state of the mucous membrane of the stomach when administered at ED50 10 mg/kg and at doses of 25 mg/kg and 100 mg/kg during one and three months, as well as the ability of dezapur, in doses exceeding the con-ditional therapeutic in 2.5 and 10 times, to intensify the detoxifying liver function, what is shown in reduction of hexenal sleep in 1.5 times respectively in one and in three months of administration.
The deep study of antihypoxic activity of dezapur on models of hypoxia of different genesis has shown that dezapur in ED50 10 mg/kg at intragastric administration has shown a pronounced antihypoxic activity at the level of 104; 134 and 206% respectively, in the model of acute histotoxic, normobaric hypercapnic and acute hypobaric hypoxia, which has shown itself not less pronounced than the comparative drug mexidol. In the model of emotional and painful stress accompanied by increased Lipid peroxidation and decreased antioxidant defense activity, the expressed inhibitory effect of dezapur on lipid peroxida-tion products has beеn established, as evidenced by a significant decrease in the myocar-dium and in serum of TBA-reaсtants; diene conjugates (DC); triene conjugates and Schiff's bases (SB); and stimulating effect on the activity of antioxidant enzyme SOD in myocardium and in erythrocytes.
In vitro, antiradical properties of dezapur and its ability to intercept oxygen radi-cals have been established; the presence of antioxidant properties is one of the mecha-nisms of its pharmacological activity: antihypoxic, antiexudative, and efficacy in the pulmonary edema model, which combines several pathogenetic units: exudation, hy-poxia, and enhancement of LPO.
