ISSN Print 2713-0894
ISSN Online 2713-0908
BIOMEDICAL JOURNAL OF ERMC EASTERN EUROPEAN
Copyright: © 2024 by the authors. Licensee: Pirogov University.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (CC BY).
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (CC BY).
ORIGINAL RESEARCH
Antirheumatic activity of 3-imidazole-substituted-4,5-diaryloisoxazol-3-carboxylic acid amide derivative, a proteinase inhibitor-activated type II receptor
About authors
1 Yaroslavl State Pedagogical University named after KD Ushinsky
2 Yaroslavl State Medical University, Yaroslavl, Russia
3 Grodno State Medical University, Grodno, Belarus
4 Russian University of Medicine, Moscow, Russia
Correspondence should be addressed: Nikita N Volkhin
Technopark str., 11/2, Yaroslavl, 150030, Russia; ur.umsy@nihklovnn
About paper
Funding: this study was supported by the Ministry of Health of the Russian Federation (state assignment 1022051600008-9-3.1.5;3.2.22) “Development of a drug for the treatment of rheumatoid arthritis and other inflammatory diseases”.
Acknowledgement: the work was carried out in collaboration with the Scientific Department of the Institute of Pharmacy of Yaroslavl State Medical University, Yaroslavl.
Author contribution: Fedorov VN — idea development, analysis and layout of the collected material; Korsakov MK — writing the text; Shetnev AA — a general idea and planning of the article, synthesis of the compound under study; Grechishcheva OV — conducting an experiment; Vdovichenko VP — collection and primary analysis of material, working with literature; Volkhin NN — conducting an experiment; Smirnov NA — primary analysis of the collected material; Khokhlova AA — collection of primary material, design of the list of references; Arshinov AV — text editing.
Compliance with ethical standards: the study was carried out in compliance with all ethical standards recommended in the Russian Federation. Rats were selected as a test system, as animals with a minimum set of characteristics that make it possible to conduct an experiment: a sufficient size of paws for convenient measurements and possibility of taking the volume of blood necessary for the study. The animals were kept in cages of sufficient area and with timely bedding change (2 times a week). Animals are provided with free access to water and food, a 12-hour lighting cycle, optimal temperature and humidity, and supervision by a licensed veterinarian. Although the research protocol did not allow to use painkillers that could distort the results of experiments, all procedures were carried out by qualified and experienced personnel, which ensured minimization of stress and pain. The animal study was preceded by in vitro studies of the drug. The power of the statistical tests used was evaluated, which made it possible to form samples of an optimal size. The animal study was approved by the Independent Ethical Committee of the Federal State Budgetary Educational Institution of Higher Education Yaroslavl State Medical University of the Ministry of Health of the Russian Federation, Protocol No. 6 dated 09/14/2023.
Received: 2024-10-29
Accepted: 2024-11-15
Published online: 2024-12-13
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Treatment of rheumatoid arthritis is a complex and time-consuming process that does not always lead to significant results both due to poor effectiveness of drugs and drug toxicity. It means we need to search for new pharmacological targets to influence the pathological process, one of which is inhibition of proteinase-activated receptors 2 (PAR2 receptors) activity. In 2016–2019, synthesis of low-molecular-weight antagonists of PAR2 receptors belonging to 4,5-dihydroisoxazole-5-carboxamide derivatives was carried out, and in 2023 their anti-inflammatory efficacy was examined using the formaldehyde edema model. The most effective laboratory R004 compound was tested on a model of autoimmune pristane-induced inflammation in rats. During treatment of chronic inflammation in rats, R004 inhibited significant development of edema of feet, damage to small joints, and specific changes in the formula of white blood, and according to biochemical blood test led to normalization of liver and kidney functions and energy metabolism. R004 turned out to be more effective and safer than the comparator drugs such as diclofenac sodium and dexamethasone.
Keywords: rheumatoid arthritis, PAR2-receptors, pristane, autoimmune inflammation, 4, 5-dihydroisoxazole-5-carboxamide amide derivative