4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors

Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges

“…9 Nomifensine (24) is another NDRI that was approved to treat depression but was later withdrawn due to safety reasons. 10 In spite of improvements in the profiles of antidepressant medications, a large unmet clinical need still exists in terms of response rate, treatment onset, residual symptoms, and side effect profile (Figure 5). As is evident from the STAR*D clinical trial, which evaluated the effectiveness of antidepressants including switching to a different medication or medication combination, only one-third of patients recover on treatment with a single antidepressant while another onethird recover only after several months of different and multiple therapy trials.…”

“…Inspired by the structure of NDRI 24 as a prototype tetrahydroisoquinoline (THIQ), AMRI explored lead optimization to identify dual inhibitors (for depression or ADHD) that were devoid of aromatic amino group in an attempt to avoid toxicity reported for 24. 10 This led to the identification of the NET/DAT inhibitor 175, which was later optimized with the aim of incorporating SERT activity (Figure 32). 125 Investigation of diverse bicyclic heteroaryl groups on the 4position of THIQ resulted in the identification of 176 incorporating a benzothiophen-5-yl group, which showed low nanomolar triple reuptake inhibitory activity but with moderate CYP2D6 inhibition (IC 50 : 0.8 μM).…”

“…While 23 also acts as a releasing agent of NE and DA, its major metabolite, hydroxybupropion, is also known to be a NET inhibitor . Nomifensine ( 24 ) is another NDRI that was approved to treat depression but was later withdrawn due to safety reasons …”

“…A NDRI/TRI discovery program that was initiated between Albany Molecular Research Incorporated (AMRI) and DuPont Pharmaceuticals was subsequently acquired by Bristol-Myers Squibb (BMS) in 2001. Inspired by the structure of NDRI 24 as a prototype tetrahydroisoquinoline (THIQ), AMRI explored lead optimization to identify dual inhibitors (for depression or ADHD) that were devoid of aromatic amino group in an attempt to avoid toxicity reported for 24 . This led to the identification of the NET/DAT inhibitor 175 , which was later optimized with the aim of incorporating SERT activity (Figure ).…”

Medicinal chemistry perspectives of 1,2,3,4-tetrahydroisoquinoline analogs – biological activities and SAR studies

“… 80–82 Molino and co-workers designed a series of THIQ analogs based on the structure of nomifensine as dual norepinephrine and dopamine reuptake inhibitors. 83 Removal of the amino group and optimization of the compounds around the THIQ core and 4-phenyl moiety resulted in the generation of compounds 207–209 ( Fig. 25 ) with good potency against norepinephrine transporter (NET) and dopamine transporter (DAT).…”