title: Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression.
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.
authors.affiliation: 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.
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Department of Neuroscience Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Neuroscience Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Bertekap
authors.affiliation: Department of Neuroscience Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Westphal
authors.affiliation: Department of Neuroscience Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Lelas
authors.affiliation: Department of Neuroscience Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Newton
authors.affiliation: Department of Neuroscience Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Wallace
authors.affiliation: Department of Neuroscience Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Taber
authors.affiliation: Department of Preclinical Candidate Optimization, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Davis
authors.affiliation: Department of Neuroscience Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Department of Neuroscience Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Bronson
mesh_terms: D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D064729:Neurokinin-1 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000928:Antidepressive Agents; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human