title: Design, optimization, and in vivo evaluation of a series of pyridine derivatives with dual NK1 antagonism and SERT inhibition for the treatment of depression.
abstract: A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.
authors.affiliation: Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. kevin.gillman@bms.com
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gillman
authors.forename: Michael F
authors.initials: MF
authors.lastname: Parker
authors.forename: Mark
authors.initials: M
authors.lastname: Silva
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Degnan
authors.forename: George O
authors.initials: GO
authors.lastname: Tora
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.forename: Snjezana
authors.initials: S
authors.lastname: Lelas
authors.forename: Matthew
authors.initials: M
authors.lastname: Taber
authors.forename: Rudolf G
authors.initials: RG
authors.lastname: Krause
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bertekap
authors.forename: Amy E
authors.initials: AE
authors.lastname: Newton
authors.forename: Rick L
authors.initials: RL
authors.lastname: Pieschl
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Lengyel
authors.forename: Kim A
authors.initials: KA
authors.lastname: Johnson
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Taylor
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D000818:Animals; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D015195:Drug Design; D005849:Gerbillinae; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines; D012702:Serotonin Antagonists