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
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Russian Journal of Bioorganic Chemistry
ISSN: 1068-1620 |
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| 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 | ||
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Abstract:
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.
Cite:
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 OpenAlex
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 OpenAlex
Original:
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 OpenAlex
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 OpenAlex
Dates:
| Submitted: | Jun 17, 2022 |
| Accepted: | Aug 12, 2022 |
| Published online: | May 3, 2023 |
Identifiers:
| Web of science: | WOS:000981909400006 |
| Scopus: | 2-s2.0-85159943992 |
| Elibrary: | 61284761 |
| OpenAlex: | W4368227899 |