title: Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.
abstract: The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
authors.affiliation: Research and Development, Eli Lilly and Company Ltd. , Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dreyfus
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Myers
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Valentina O
authors.initials: VO
authors.lastname: Badescu
authors.affiliation: Lilly S.A. , Centro de Investigación, Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: de Frutos
authors.affiliation: Lilly S.A. , Centro de Investigación, Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain.
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: de la Puente
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Chunjin
authors.initials: C
authors.lastname: Ding
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Filla
authors.affiliation: Covance, Inc. , Greenfield, Indiana 46140, United States.
authors.forename: Karsten
authors.initials: K
authors.lastname: Fynboe
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Gernert
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Heinz
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Hemrick-Luecke
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Kirk W
authors.initials: KW
authors.lastname: Johnson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Johnson
authors.affiliation: Lilly S.A. , Centro de Investigación, Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: López
authors.affiliation: Covance, Inc. , Greenfield, Indiana 46140, United States.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Love
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Thierry
authors.initials: T
authors.lastname: Masquelin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCoy
authors.affiliation: Lilly S.A. , Centro de Investigación, Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Mendiola
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Denise
authors.initials: D
authors.lastname: Morrow
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Muhlhauser
authors.affiliation: Lilly S.A. , Centro de Investigación, Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Pascual
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Perun
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Pfeifer
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Phebus
authors.affiliation: Research and Development, Eli Lilly and Company Ltd. , Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Richards
authors.affiliation: Lilly S.A. , Centro de Investigación, Avda. de la Industria, 30, Alcobendas-Madrid 28108, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Rincón
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Seest
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Jikesh
authors.initials: J
authors.lastname: Shah
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Jia
authors.initials: J
authors.lastname: Shaojuan
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Rosa Maria A
authors.initials: RM
authors.lastname: Simmons
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Stephenson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Tromiczak
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Thompson
authors.affiliation: Research and Development, Eli Lilly and Company Ltd. , Sunninghill Road, Windlesham, Surrey GU20 6PH, United Kingdom.
authors.forename: Magnus W
authors.initials: MW
authors.lastname: Walter
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Weber
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Hamideh
authors.initials: H
authors.lastname: Zarrinmayeh
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Thomas
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joshi
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Smriti
authors.initials: S
authors.lastname: Iyengar
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Anette M
authors.initials: AM
authors.lastname: Johansson
keywords: NET; SERT; SERT RO; SNRI; dual; pain; reuptake inhibitor; α-MMT