Discovery of DSP-1053, a novel benzylpiperidine derivative with potent serotonin transporter inhibitory activity and partial 5-HT1A receptor agonistic activity

Hidefumi Yoshinaga; Tomoaki Nishida; Izumi Sasaki; Taro Kato; Hitomi Oki; Kazuki Yabuuchi; Tomohiro Toyoda

doi:10.1016/j.bmc.2018.02.008

Discovery of DSP-1053, a novel benzylpiperidine derivative with potent serotonin transporter inhibitory activity and partial 5-HT_1A receptor agonistic activity

Bioorg Med Chem. 2018 May 1;26(8):1614-1627. doi: 10.1016/j.bmc.2018.02.008. Epub 2018 Feb 8.

Authors

Hidefumi Yoshinaga¹, Tomoaki Nishida², Izumi Sasaki², Taro Kato², Hitomi Oki², Kazuki Yabuuchi², Tomohiro Toyoda²

Affiliations

¹ Drug Research Division, Sumitomo Dainippon Pharma CO., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address: hidefumi-yoshinaga@ds-pharma.co.jp.
² Drug Research Division, Sumitomo Dainippon Pharma CO., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.

PMID: 29456112
DOI: 10.1016/j.bmc.2018.02.008

Abstract

We have previously shown that SMP-304, a serotonin uptake inhibitor with weak 5-HT_1A partial agonistic activity, may act under high serotonin levels as a 5-HT_1A antagonist that improves the onset of paroxetine in the rat swimming test. However, SMP-304 is mostly metabolized by CYP2D6, indicating limited efficacy among individuals and increased side effects. To reduce CYP2D6 metabolic contribution and enhance SERT/5-HT_1A binding affinity, we carried out a series of substitutions at the bromine atom in the left part of the benzene ring of SMP-304 and replaced the right part of SMP-304 with a chroman-4-one. This optimization work led to the identification of the antidepressant candidate DSP-1053 as a potent SERT inhibitor with partial 5-HT_1A receptor agonistic activity. DSP-1053 showed low CYP2D6 metabolic contribution and a robust increase in serotonin levels in the rat frontal cortex.

Keywords: 5-HT(1A) receptor; Antidepressant; Benzylpiperidine; CYP2D6; Fast onset; Serotonin transporter.

MeSH terms

Animals
Dose-Response Relationship, Drug
Drug Discovery
Humans
Male
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Rats
Receptor, Serotonin, 5-HT1A / metabolism*
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / chemistry
Selective Serotonin Reuptake Inhibitors / pharmacology*
Serotonin 5-HT1 Receptor Agonists / chemical synthesis
Serotonin 5-HT1 Receptor Agonists / chemistry
Serotonin 5-HT1 Receptor Agonists / pharmacology*
Serotonin Plasma Membrane Transport Proteins / metabolism*
Structure-Activity Relationship

Substances

Piperidines
Serotonin 5-HT1 Receptor Agonists
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors
Receptor, Serotonin, 5-HT1A