Experimental Assessment of 3-meta-Pyridine-1,2,4-Oxadiazole Deoxycholic Acid Derivative as a Prototype of 5-α-Reductase Inhibitors in silico and in vivo Models
- Autores: Meshkova Y.1, Baev D.1, Sorokina I.1, Popadyuk I.1, Salomatina O.1, Zhukova N.1, Tolstikova T.1, Salakhutdinov N.1
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Afiliações:
- Novosibirsk Institute of Organic Chemistry SB RAS
- Edição: Volume 49, Nº 1 (2023)
- Páginas: 79-92
- Seção: Articles
- URL: https://journals.rcsi.science/0132-3423/article/view/145870
- DOI: https://doi.org/10.31857/S0132342323010189
- EDN: https://elibrary.ru/GGKQXV
- ID: 145870
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Resumo
5-α-Reductase (5-AR) inhibitors are considered the most effective drugs in the treatment of proliferative processes in prostate adenoma. These include two synthetic azasteroids – finasteride and dutasteride, which cause side effects in conditions of long-term course therapy which form the disorders of sexual function in men. We propose 3-meta-pyridine-1,2,4-oxadiazole derivative of deoxycholic acid as prototype of low-toxic 5-AR inhibitors. It has been shown that the new agent is able to penetrate the 5-AR binding site through the formation of covalent adducts with NADP-H, like finasteride. At the same time, both ligands have comparable with the target binding energy values (–20 and –15 kcal/mol, respectively, for finasteride and target compound). In experiments on testosterone and sulpiride models of BPH, we have found that intragastric administration of DCA derivative at a dose of 20 mg/kg and finasteride at a dose of 10 mg/kg has a similar prostatoprotective effect by reducing proliferative processes in the glandular epithelium and prostate stroma of rats. The new agent is less toxic than finasteride: the LD50 value in mice is >1500 mg/kg versus 1060 mg/kg in finasteride. Based on the results obtained, the 3-meta-pyridine-1,2,4-oxadiazole derivative of deoxycholic acid can be considered as a promising candidate for preclinical testing.
Sobre autores
Yu. Meshkova
Novosibirsk Institute of Organic Chemistry SB RAS
Email: sorokina.irina55@gmail.com
Russia, 630090, Novosibirsk, prosp. Lavrentieva 9
D. Baev
Novosibirsk Institute of Organic Chemistry SB RAS
Email: sorokina.irina55@gmail.com
Russia, 630090, Novosibirsk, prosp. Lavrentieva 9
I. Sorokina
Novosibirsk Institute of Organic Chemistry SB RAS
Autor responsável pela correspondência
Email: sorokina.irina55@gmail.com
Russia, 630090, Novosibirsk, prosp. Lavrentieva 9
I. Popadyuk
Novosibirsk Institute of Organic Chemistry SB RAS
Email: sorokina.irina55@gmail.com
Russia, 630090, Novosibirsk, prosp. Lavrentieva 9
O. Salomatina
Novosibirsk Institute of Organic Chemistry SB RAS
Email: sorokina.irina55@gmail.com
Russia, 630090, Novosibirsk, prosp. Lavrentieva 9
N. Zhukova
Novosibirsk Institute of Organic Chemistry SB RAS
Email: sorokina.irina55@gmail.com
Russia, 630090, Novosibirsk, prosp. Lavrentieva 9
T. Tolstikova
Novosibirsk Institute of Organic Chemistry SB RAS
Email: sorokina.irina55@gmail.com
Russia, 630090, Novosibirsk, prosp. Lavrentieva 9
N. Salakhutdinov
Novosibirsk Institute of Organic Chemistry SB RAS
Email: sorokina.irina55@gmail.com
Russia, 630090, Novosibirsk, prosp. Lavrentieva 9
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