title: The Discovery and Hit-to-Lead Optimization of Tricyclic Sulfonamides as Potent and Efficacious Potentiators of Glycine Receptors.
abstract: Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well as abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission of painful stimuli. Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic sulfonamides as allosteric GlyR potentiators. Initial optimization of high-throughput screening (HTS) hit 1 led to the identification of 3, which demonstrated ex vivo potentiation of glycine-activated current in mouse dorsal horn neurons from spinal cord slices. Further improvement of potency and pharmacokinetics produced in vivo proof-of-concept tool molecule 20 (AM-1488), which reversed tactile allodynia in a mouse spared-nerve injury (SNI) model. Additional structural optimization provided highly potent potentiator 32 (AM-3607), which was cocrystallized with human GlyRα3crystto afford the first described potentiator-bound X-ray cocrystal structure within this class of ligand-gated ion channels (LGICs).
authors.forename: Howard
authors.identifier: 0000-0001-8062-9770
authors.initials: H
authors.lastname: Bregman
authors.affiliation: Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Simard
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.forename: Shawn
authors.initials: S
authors.lastname: Ayube
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Jiali
authors.initials: J
authors.lastname: Hu
authors.forename: Liyue
authors.initials: L
authors.lastname: Huang
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Paul H
authors.initials: PH
authors.lastname: Krolikowski
authors.affiliation: Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lewis
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.forename: Pamela
authors.initials: P
authors.lastname: Pegman
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Plant
authors.forename: Paul L
authors.initials: PL
authors.lastname: Shaffer
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.forename: Shuyan
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Zhang
authors.forename: Jacinthe
authors.initials: J
authors.lastname: Gingras
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018009:Receptors, Glycine / Q000819:agonists*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D018009:Receptors, Glycine; D013449:Sulfonamides