Synthesis and activity of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors

Synthesis and in Silico Evaluation of Novel Compounds for PET-Based Investigations of the Norepinephrine Transporter

“…Fluorination at position 2 of the phenyl moiety attached to the benzimidazolone ring (e.g., 2, Figure 1), indicated similar hNET potency, comparable to its non-fluorinated analogs (e.g., 1) and additionally exhibited hNET selectivity over hSERT (80-fold) similar to atomoxetine [26]. Both benzimidazolone derived propanamines with a phenyl moiety (e.g., 1), as well as a fluorinated phenyl moiety (as in 2) indicated excellent hNET selectivity over human dopamine transporter (hDAT) with < 50% inhibition of the cocaine analog [ 3 H]WIN-35,428, binding to hDAT at a concentration of 10 µM [26]. Given those findings, both described benzimidazolone-based propanamines 1 and 2 represent excellent candidates for selective and potent NET inhibition with high affinity and low unspecific binding.…”

“…So far, radiolabeled NET binding reboxetine analogs [ ]methoxyphenoxy)benzyl)morpholine) have been described, which however display certain limitations such as metabolic instability, complex radiosyntheses, or late equilibria [22][23][24][25][26].…”

“…Recently, Zhang et al [26] evaluated a series of benzimidazolone-based propanamines with in vitro inhibitory activity on the human norepinephrine transporter (hNET). The results of these investigations suggested that compounds containing a phenyl moiety directly attached at the benzimidazolone ring (e.g., 1, Figure 1) were the most potent, representing a half maximal inhibitory concentration (IC50) below 10 nM (IC50 < 10 nM).…”

“…The results of these investigations suggested that compounds containing a phenyl moiety directly attached at the benzimidazolone ring (e.g., 1, Figure 1) were the most potent, representing a half maximal inhibitory concentration (IC50) below 10 nM (IC50 < 10 nM). Furthermore, hNET selectivity over human serotonin transporter (hSERT) turned out >300-fold superior to those of reboxetine and atomoxetine (16-and 81-fold) [26]. Fluorination at position 2 of the phenyl moiety attached to the benzimidazolone ring (e.g., 2, Figure 1), indicated similar hNET potency, comparable to its non-fluorinated analogs (e.g., 1) and additionally exhibited hNET selectivity over hSERT (80-fold) similar to atomoxetine [26].…”

“…Furthermore, hNET selectivity over human serotonin transporter (hSERT) turned out >300-fold superior to those of reboxetine and atomoxetine (16-and 81-fold) [26]. Fluorination at position 2 of the phenyl moiety attached to the benzimidazolone ring (e.g., 2, Figure 1), indicated similar hNET potency, comparable to its non-fluorinated analogs (e.g., 1) and additionally exhibited hNET selectivity over hSERT (80-fold) similar to atomoxetine [26]. Both benzimidazolone derived propanamines with a phenyl moiety (e.g., 1), as well as a fluorinated phenyl moiety (as in 2) indicated excellent hNET selectivity over human dopamine transporter (hDAT) with < 50% inhibition of the cocaine analog [ 3 H]WIN-35,428, binding to hDAT at a concentration of 10 µM [26].…”