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Experimental Evaluation of 3-meta-Pyridine-1,2,4-Oxadiazole Derivative of Deoxycholic Acid as a Prototype of 5-α-Reductase Inhibitors in In Silico and In Vivo Models

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Abstract—

It is considered that 5-α-reductase (5-AR) inhibitors are the most effective drugs for suppressing proliferative processes in prostate adenoma. They include two synthetic azasteroids, finasteride and dutasteride, which exert side effects in the form of sexual function disorders in the men undergoing long-term therapy. We have proposed deoxycholic acid as the starting compound for the synthesis of low-toxic 5-AR inhibitors. A target compound containing the 3-meta-pyridine-1,2,4-oxadiazole fragment was synthesized on its basis. Using molecular docking it has been demonstrated that the newly obtained agent is able to enter the 5-AR binding site through the formation of covalent adducts with NADP-H like finasteride does. Both ligands have comparable target binding energies (–20 and –15 kcal/mol for finasteride and the target compound, respectively). In the experiments on testosterone and sulpiride benign prostatic hyperplasia models it was shown that intragastric administration of the obtained deoxycholic acid derivative at a dose of 20 mg/kg and finasteride at a dose of 10 mg/kg to Wistar rats have similar prostate protection effects consisting in the reduction of proliferative processes in the glandular epithelium and prostate stroma of rats. The new agent is less toxic than finasteride: LD50 in CD-1 mice is >1500 mg/kg versus 1060 mg/kg in the case of finasteride. Based on the results the 3-meta-pyridine-1,2,4-oxadiazole derivative of deoxycholic acid can be considered as a promising candidate for preclinical trials.

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ACKNOWLEDGMENTS

The authors are grateful to the Chemical Research Center for Collective Use of the Siberian Branch of the Russian Academy of Sciences (CCU) for conducting spectral and analytical measurements.

Funding

The work was supported by the Basic Research Projects Support Program of the Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences (grant nos. 1021051402785-4-1.4.1 and 1021051703312-0-1.4.1).

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Authors and Affiliations

  1. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk, Russia

    Yu. V. Meshkova, D. S. Baev, I. V. Sorokina, I. I. Popadyuk, O. V. Salomatina, N. A. Zhukova, T. G. Tolstikova & N. F. Salakhutdinov

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  1. Yu. V. Meshkova
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  2. D. S. Baev
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  3. I. V. Sorokina
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  4. I. I. Popadyuk
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  5. O. V. Salomatina
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  6. N. A. Zhukova
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  7. T. G. Tolstikova
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  8. N. F. Salakhutdinov
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Correspondence to I. V. Sorokina.

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Conflict of interest. The authors declare no conflicts of interest.

Statement on the welfare of animals. All manipulations with animals were performed in strict compliance with the Russian legislation, the Order of the Russian Ministry of Healthcare No. 199n issued April 1, 2015, and the provisions of Directive no. 2010/63/EU of the European Parliament and the Council of the European Union issued September 22, 2010, on the protection of animals involved in scientific experimentation.

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Translated by E. Martynova

Abbreviations: 5-AR, 5-α-reductase; 5-ARI, 5-α-reductase inhibitors; BPH, benign prostatic hyperplasia; DHT– dihydrotestosterone; DCA, deoxycholic acid, and LD50, mean dose causing death of half of the test group.

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Meshkova, Y.V., Baev, D.S., Sorokina, I.V. et al. Experimental Evaluation of 3-meta-Pyridine-1,2,4-Oxadiazole Derivative of Deoxycholic Acid as a Prototype of 5-α-Reductase Inhibitors in In Silico and In Vivo Models. Russ J Bioorg Chem 49, 52–64 (2023). https://doi.org/10.1134/S1068162023010181

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