Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression

Yong-Jin Wu; Huan He; Robert Bertekap; Ryan Westphal; Snjezana Lelas; Amy Newton; Tanya Wallace; Matthew Taber; Carl Davis; John E Macor; Joanne Bronson

doi:10.1016/j.bmc.2013.02.010

Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression

Bioorg Med Chem. 2013 Apr 15;21(8):2217-2228. doi: 10.1016/j.bmc.2013.02.010. Epub 2013 Feb 19.

Authors

Affiliations

¹ Department of Neuroscience Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: yong-jin.wu@bms.com.
² Department of Neuroscience Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
³ Department of Neuroscience Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
⁴ Department of Preclinical Candidate Optimization, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.

PMID: 23477943
DOI: 10.1016/j.bmc.2013.02.010

Abstract

This report describes the synthesis, structure-activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.

MeSH terms

Antidepressive Agents / chemistry
Antidepressive Agents / pharmacology
Astrocytes / cytology
Astrocytes / drug effects
Cell Line
HEK293 Cells
Humans
Neurokinin-1 Receptor Antagonists / chemistry*
Neurokinin-1 Receptor Antagonists / pharmacology*
Piperidines / chemical synthesis
Piperidines / chemistry*
Piperidines / pharmacology*
Receptors, Neurokinin-1 / metabolism
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / chemistry*
Selective Serotonin Reuptake Inhibitors / pharmacology*
Serotonin Plasma Membrane Transport Proteins / biosynthesis
Serotonin Plasma Membrane Transport Proteins / genetics
Structure-Activity Relationship

Substances

Antidepressive Agents
Neurokinin-1 Receptor Antagonists
Piperidines
Receptors, Neurokinin-1
SLC6A4 protein, human
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors