Propylamines and piperidines as triple serotonin, norepinephrine and dopamine reuptake inhibitors: design, synthesis and structure-activity relationships

Abstract

The discovery of new highly potent and selective serotonin (5-HT), norepinephrine (NE), and dopamine (DA) triple reuptake inhibitors (TRIs or SNDRIs) is reported. From the library of SK compound collection, dimethyl-(3-carbamoyloxy-3-naphthalen-2-yl-propyl)-amine 27 as having micromolar binding affinity for the cerebral rat serotonin transporter was identified. Introduction of a carbamoyloxy group revealed a significant effect of functionality about the 3 and 4 position of the phenyl ring on 5-HT activity and led to the discovery of an azole compound 30 which have alternate isostere of carbamoyloxy group. Structure-activity relationship (SAR) studies were performed via variation of azole and aryl group of a series of 3-aryl-3-azolylpropan-1-amine derivatives. Based on the outcomes of in vitro studies and in animal models, 49r was identified as a lead compound. An emerging understanding of the SAR within these propylamine and 3-piperidine scaffolds showed that the naphthyl ring played an important role in modulating SRI activity. The DAT, NET and SERT potencies are sensitive to electronic and steric modifications on the naphthyl and azolyl ring, and affinities toward these transporters can be tuned by careful choice of substituents and chirality. From this analysis, 60b emerged as optimized lead with superior triple reuptake inhibition activity. 49r and 60b were evaluated in additional pharmacophore modeling, pharmacology, pharmacokinetics studies as representative examples from this series.