Experimental Assessment of 3-<i>meta</i>-Pyridine-1,2,4-Oxadiazole Deoxycholic Acid Derivative as a Prototype of 5-α-Reductase Inhibitors <i>in silico</i> and <i>in vivo</i> Models

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.