title: Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design.
abstract: In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Spencer B
authors.initials: SB
authors.lastname: Jones
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Pfeifer
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bleisch
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Beauchamp
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Jim D
authors.initials: JD
authors.lastname: Durbin
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: V Joseph
authors.initials: VJ
authors.lastname: Klimkowski
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Hughes
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rito
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Yen
authors.initials: Y
authors.lastname: Dao
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Gruber
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Hai
authors.initials: H
authors.lastname: Bui
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Chambers
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Chandrasekhar
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Chaohua
authors.initials: C
authors.lastname: Lin
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Denis J
authors.initials: DJ
authors.lastname: McCann
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Mudra
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Oskins
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Swearingen
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Kannan
authors.initials: K
authors.lastname: Thirunavukkarasu
authors.affiliation: Lilly Research Laboratories , A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Norman
keywords: Autotaxin; LPA; osteoarthritis; tool molecule