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

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 Full article

Journal

Russian Journal of Bioorganic Chemistry
ISSN: 1068-1620

Output data

Year: 2023, Volume: 49, Number: 1, Pages: 52-64 Pages count : 13 DOI: 10.1134/s1068162023010181

Tags

5-α-reductase inhibitors, deoxycholic acid oxadiazole derivatives, toxicity, benign prostatic hyperplasia, rats

Authors

Meshkova Yu.V. ¹ , Baev D.S. ¹ , Sorokina I.V. ¹ , Popadyuk I.I. ¹ , Salomatina O.V. ¹ , Zhukova N.A. ¹ , Tolstikova T.G. ¹ , Salakhutdinov N.F. ¹

Affiliations

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

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.

Meshkova Y.V. , Baev D.S. , Sorokina I.V. , Popadyuk I.I. , Salomatina O.V. , Zhukova N.A. , Tolstikova T.G. , Salakhutdinov N.F.
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
Russian Journal of Bioorganic Chemistry. 2023. V.49. N1. P.52-64. DOI: 10.1134/s1068162023010181 WOS Scopus РИНЦ

Мешкова Ю.В. , Баев Д.С. , Сорокина И.В. , Попадюк И.И. , Саломатина О.В. , Жукова Н.А. , Толстикова Т.Г. , Салахутдинов Н.Ф.
ЭКСПЕРИМЕНТАЛЬНАЯ ОЦЕНКА 3-МЕТА-ПИРИДИН-1,2,4-ОКСАДИАЗОЛЬНОГО ПРОИЗВОДНОГО ДЕЗОКСИХОЛЕВОЙ КИСЛОТЫ КАК ПРОТОТИПА ИНГИБИТОРОВ 5-α-РЕДУКТАЗЫ В МОДЕЛЯХ IN SILICO И IN VIVO
Биоорганическая химия (RUSS J BIOORG CHEM+). 2023. Т.49. №1. С.79-92. DOI: 10.31857/S0132342323010189 РИНЦ

Submitted:	Jun 17, 2022
Accepted:	Aug 12, 2022
Published online:	May 3, 2023

Web of science	WOS:000981909400006
Scopus	2-s2.0-85159943992
Elibrary	61284761
OpenAlex	W4368227899