2. Academic Validation
  3. The Discovery and Hit-to-Lead Optimization of Tricyclic Sulfonamides as Potent and Efficacious Potentiators of Glycine Receptors

The Discovery and Hit-to-Lead Optimization of Tricyclic Sulfonamides as Potent and Efficacious Potentiators of Glycine Receptors

  • J Med Chem. 2017 Feb 9;60(3):1105-1125. doi: 10.1021/acs.jmedchem.6b01496.
Howard Bregman,  Jeffrey R Simard 1,  Kristin L Andrews,  Shawn Ayube,  Hao Chen,  Hakan Gunaydin,  Angel Guzman-Perez,  Jiali Hu,  Liyue Huang,  Xin Huang,  Paul H Krolikowski,  Sonya G Lehto 1,  Richard T Lewis,  Klaus Michelsen,  Pamela Pegman,  Matthew H Plant,  Paul L Shaffer,  Yohannes Teffera,  Shuyan Yi,  Maosheng Zhang 1,  Jacinthe Gingras,  Erin F DiMauro
Affiliations

Affiliation

  • 1 Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
PMID: 28001399 DOI: 10.1021/acs.jmedchem.6b01496
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 GlyRα3cryst to afford the first described potentiator-bound X-ray cocrystal structure within this class of ligand-gated ion channels (LGICs).

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