Prospects for the creation of new drug candidates with antidepressant activity among thietanes

Abstract

The article presents the results of systematic studies on the search for new biologically active molecules with antidepressant activity in the series of thietane-containing heterocyclic compounds and 3-substituted thietane dioxides. The used strategy for the search for antidepressant substances, based on in vivo pharmacological screening in combination with in silico methods of mathematical modeling and toxico-pharmacokinetic evaluation, is described. Studies of the biological activity of thietane-containing reaction products of azoles with thiiranes have been carried out in the series of thietanylimidazoles, titanixanthines, thietanyltriazoles, thietanyltriazolones, and 3-substituted thietane-1,1-dioxides (more than 300 compounds have been studied). The main results of the preclinical evaluation of promising drug candidates with antidepressant activity, 3-methoxythiethane-1,1-dioxide and 3-ethoxythiethane-1,1-dioxide, are presented. Both 3-substituted thietane-1,1-dioxides are characterized by low toxicity when administered intraperitoneally to mice (class IV low toxicity), the absence of toxic risks (mutagenic, carcinogenic, reproductive toxicity, local irritant action), high pharmaceutical potential (compliance with the rule of five Lipinsky), a wide range of action and pronounced antidepressant activity, not inferior to the reference drug amitriptyline (10 mg/kg), confirmed in highly valid in vivo models of depressive-like states (chronic mild stress and resident intruder). In tests of neuropharmacological interaction, it was found that the proposed mechanism of action of 3-substituted thietane-1,1-dioxides is associated with stimulation of 5-HT1A receptors, blockade of 5-HT2A/2C receptors and/or 2-adrenergic receptors. The need for further research is substantiated in order to create domestic first in class antidepressants on their basis.