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

Yu. V. Meshkova; Мешкова Ю. В.; D. S. Baev; Баев Д. С.; I. V. Sorokina; Сорокина И. В.; I. I. Popadyuk; Попадюк И. И.; O. V. Salomatina; Саломатина О. В.; N. A. Zhukova; Жукова Н. А.; T. G. Tolstikova; Толстикова Т. Г.; N. F. Salakhutdinov; Салахутдинов Н. Ф.

doi:10.31857/S0132342323010189

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

Authors: Meshkova Y.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. Novosibirsk Institute of Organic Chemistry SB RAS
Issue: Vol 49, No 1 (2023)
Pages: 79-92
Section: Articles
URL: https://rjmseer.com/0132-3423/article/view/670708
DOI: https://doi.org/10.31857/S0132342323010189
EDN: https://elibrary.ru/GGKQXV
ID: 670708

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Abstract

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.

Keywords

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

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