期刊
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY
卷 49, 期 1, 页码 52-64出版社
MAIK NAUKA/INTERPERIODICA/SPRINGER
DOI: 10.1134/S1068162023010181
关键词
5-alpha-reductase inhibitors; deoxycholic acid oxadiazole derivatives; toxicity; benign prostatic hyperplasia; rats
A low-toxic 5-AR inhibitor was synthesized based on deoxycholic acid, which showed similar prostate protection effects to finasteride but with lower toxicity. The compound demonstrated promising potential as a candidate for preclinical trials.
It is considered that 5-a-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据