Current Approaches to the Preclinical Assessment of Endocrine Toxicity

Scientific relevance. Endocrine disruptors affect the functioning of endocrine organs, which leads to adverse drug reactions. Endocrine toxicity requires special attention in preclinical studies of candidate medicinal products.Aim. The study aimed to review international guidelines and approaches to assessing the risk of endocrine toxicity associated with medicinal products.Discussion. This review covers documents that provide a methodological framework for identifying and classifying a chemical compound as an endocrine disruptor. These documents include the following: Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption (Organisation for Economic Cooperation and Development, 2018), Nonclinical Evaluation of Endocrine-Related Drug Toxicity (Food and Drug Administration, 2015), and Guidance for the Identification of Endocrine Disruptors in the Context of Regulations (EU) No. 528/2012 and (EC) No. 1107/2009. The proposed algorithm for endocrine toxicity assessment involves collecting all available data on the test compound, such as the literature and previously obtained experimental data, including acute and subchronic toxicity data, and in silico predictions. Particular attention should be paid to the standard battery of preclinical chronic toxicity studies, which can identify most side effects associated with the endocrine system. The main endpoints for endocrine toxicity include changes in the mass and histopathology of the major endocrine organs (adrenal glands, testes, epididymides, ovaries, and the thyroid gland), oestrous cycle effects, reproductive toxicity, and transplacental action. A thorough assessment of the data obtained provides for the determination of unfavourable endocrine activity that requires further studies.Conclusions. The OECD guidelines offer a set of validated in vivo and in vitro tests that characterise the most important mechanisms of endocrine toxicity (oestrogen, androgen, thyroid, and steroidogenic endocrine pathways) by identified toxic effects. This approach allows researchers to identify potential endocrine disorders early in the drug development process and to optimise the scope of the required studies accordingly

Azoloazines as Perspective Antiglycating Agents for Therapy of Diabetes Complications

This work was supported by Russian Federation Ministry of education and science (grant № 4.6351.2017/8.9) and Russian Foundation for Basic Research (grant № 18-03-00787)

Discovery of Nitro-azolo[1,5-a]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury

Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit LPS-induced NO synthesis and interleukin 6 (IL-6) secretion. We identified lead compound 9g that inhibits IL-6 secretion with IC50 of 3.72 µM without apparent cytotoxicity and with minimal suppression of macrophage phagocytosis in contrast to dexamethasone. In a mouse model of LPS-induced acute lung injury, 30 mg/kg i.p. 9g ameliorated anxiety-like behavior, inhibited IL-6 release, and limited neutrophil infiltration and pulmonary edema. A histological study confirmed the protective activity of 9g. Treatment with compound 9g prevented the migration of CD68+ macrophages and the incidence of hemorrhage. Hence, we have identified a promising pharmacological approach for the treatment of acute lung injury that may hold promise for the development of novel drugs against cytokine-mediated complications of bacterial and viral infections. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Ministry of Education and Science of the Russian Federation, Minobrnauka: 075-15-2020-777Funding: This research was funded by the Ministry of Science and Higher Education of the Russian Federation (Agreement on the provision of grants from the federal budget in the form of subsidies under paragraph 4 of Article 78.1 of the Budget Code of the Russian Federation, Moscow, 1 October 2020 No. 075-15-2020-777)

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

© 2017 The Author(s). Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD 50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity

CK2 Inhibition and Antitumor Activity of 4,7-Dihydro-6-nitroazolo[1,5-a]pyrimidines

Today, cancer is one of the most widespread and dangerous human diseases with a high mortality rate. Nevertheless, the search and application of new low-toxic and effective drugs, combined with the timely diagnosis of diseases, makes it possible to cure most types of tumors at an early stage. In this work, the range of new polysubstituted 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines was extended. The structure of all the obtained compounds was confirmed by the data of 1H, 13C NMR spectroscopy, IR spectroscopy, and elemental analysis. These compounds were evaluated against human recombinant CK2 using the ADP-GloTM assay. In addition, the IC50 parameters were calculated based on the results of the MTT test against glioblastoma (A-172), embryonic rhabdomyosarcoma (Rd), osteosarcoma (Hos), and human embryonic kidney (Hek-293) cells. Compounds 5f, 5h, and 5k showed a CK2 inhibitory activity close to the reference molecule (staurosporine). The most potential compound in the MTT test was 5m with an IC50 from 13 to 27 µM. Thus, our results demonstrate that 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines are promising for further investigation of their antitumor properties. © 2022 by the authors.Ministry of Education and Science of the Russian Federation, Minobrnauka: FEUZ-2020–0058, H687.42B.223/20This work was financially supported by the Ministry of Science and Higher Education of the Russian Federation, State Contract № FEUZ-2020–0058 (H687.42B.223/20)

New antiglycating agents for diabetes therapy

It was shown that azoloazines (1) demonstrated higher antiglycation activity than reference compound, aminoguanidine, and have some potential as dipeptidylpeptidase-4 inhibitors. By given results this class of heterocycles can be considered as candidate for extended studies to develop drugs against complications of T2DM [1-4].The work was supported by the Ministry of Education and Science of Russia (grant №0836-2020-0058)

Pyridoxine dipharmacophore derivatives as potent glucokinase activators for the treatment of type 2 diabetes mellitus

© 2017 The Author(s). Glucokinase is one of the promising targets for glucose-lowering agents, and the development of GK activators are now considered as one of the most promising strategies for the treatment of type 2 diabetes mellitus. In this work, a series of novel symmetric molecular constructs, in which two pyridoxine moieties are connected via sulfur-containing linkers, have been synthesized and tested in vitro for glucokinase activation potential. The enzyme activation rates by two most active compounds at 100 μM (~150% and 130%) were comparable to that of the reference agent PF-04937319 (~154%). Both leading compounds demonstrated low cytotoxicity and excellent safety profile in acute toxicity experiment in rats after oral administration with LD 50 exceeding 2000 mg/kg of body weight. Binding mode of the active compounds in comparison with the reference agent was studied using molecular docking. The leading compounds represent viable preclinical candidates for the treatment of type 2 diabetes mellitus, as well as a promising starting point for the design of structural analogs with improved activity

3-Arylidene-2-oxindoles as Potent NRH:Quinone Oxidoreductase 2 Inhibitors

The enzyme NRH:quinone oxidoreductase 2 (NQO2) plays an important role in the pathogenesis of various diseases such as neurodegenerative disorders, malaria, glaucoma, COVID-19 and cancer. NQO2 expression is known to be increased in some cancer cell lines. Since 3-arylidene-2-oxindoles are widely used in the design of new anticancer drugs, such as kinase inhibitors, it was interesting to study whether such structures have additional activity towards NQO2. Herein, we report the synthesis and study of 3-arylidene-2-oxindoles as novel NRH:quinone oxidoreductase inhibitors. It was demonstrated that oxindoles with 6-membered aryls in the arylidene moiety were obtained predominantly as E-isomers while for some 5-membered aryls, the Z-isomers prevailed. The most active compounds inhibited NQO2 with an IC50 of 0.368 µM. The presence of a double bond in the oxindoles was crucial for NQO2 inhibition activity. There was no correlation between NQO2 inhibition activity of the synthesized compounds and their cytotoxic effect on the A549 cell line