Vortioxetine Derivatives with Amino Acid as Promoiety: Synthesis, Activity, Stability and Preliminary Pharmacokinetic...

Vortioxetine (Vot) is an effective antidepressant with unique mechanisms exerting multi-target effects. However, severe side-effects such as nausea and vomiting are commonly experienced under conditions of long-term administration. Eight amino acid modified Vot derivatives were designed and prepared in this study. Similar or lower binding affinities of the modified compounds to the serotonin transporter (SERT) than Vot was observed in the 4-(4-(dimethylamino)-styrl)-N-methylpyridinium (ASP⁺) uptake assay on RBL-2H3 cells. Additionally, the majority of derivatives remained sufficiently stable in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), indicating achievement of intestinal absorption in the modified form. Afterwards, all derived compounds exhibited slower hepatic clearance and a longer half-life, compared to the parent drug Vot. Notably, threonine-modified 3f exhibited significantly lower activity to SERT, serine-modified 3e showed the fastest degradation rate in rat plasma, with hydrolysis to an extent of 50% in 10 min, and better pharmacokinetic properties in rat, including C_max, t_1/2, and especially AUC_0-t, which was ~3-fold higher relative to the parent compound. Although, no clear understanding of SARs has been obtained, modification of Vot with amino acids containing hydroxyl groups may be beneficial to reduce the gastrointestinal side effect of Vot or obtain better pharmacokinetic properties, providing some ideas for the further study in the future.