title: Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors.
abstract: Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection.
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: andrew.degnan@bms.com.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Degnan
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: George O
authors.initials: GO
authors.lastname: Tora
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Rajamani
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Bertekap
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Rudolph
authors.initials: R
authors.lastname: Krause
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Davis
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Joanna
authors.initials: J
authors.lastname: Hu
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morgan
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Taylor
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Kelly
authors.initials: K
authors.lastname: Krause
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Gail
authors.initials: G
authors.lastname: Mattson
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Cunningham
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Taber
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gillman
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D005849:Gerbillinae; D006801:Humans; D064729:Neurokinin-1 Receptor Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D001713:Biphenyl Compounds; D064729:Neurokinin-1 Receptor Antagonists; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: NK(1); Neurokin 1; Neuroscience discovery; SERT; SSRI; Serotonin transport inhibitors