The Discovery and Hit-to-Lead Optimization of Tricyclic Sulfonamides as Potent and Efficacious Potentiators of Glycine Receptors
| Autor: | Shawn Ayube, Hao Chen, Yohannes Teffera, Jacinthe Gingras, Paul L. Shaffer, Paul Krolikowski, Angel Guzman-Perez, Kristin L. Andrews, Hakan Gunaydin, Richard Thomas Lewis, Klaus Michelsen, Jiali Hu, Liyue Huang, Sonya G. Lehto, Pamela Pegman, Erin F. DiMauro, Howard Bregman, Shuyan Yi, Xin Huang, Maosheng Zhang, Matthew H. Plant, Jeffrey R. Simard |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Allosteric regulation Pharmacology In Vitro Techniques Inhibitory postsynaptic potential 03 medical and health sciences Mice 0302 clinical medicine Receptors Glycine In vivo Drug Discovery Animals Humans Glycine receptor chemistry.chemical_classification Sulfonamides Chemistry Hit to lead Potentiator Mice Inbred C57BL 030104 developmental biology HEK293 Cells Molecular Medicine 030217 neurology & neurosurgery Ex vivo Tricyclic |
| Zdroj: | Journal of medicinal chemistry. 60(3) |
| ISSN: | 1520-4804 |
| Popis: | 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 descri... |
| Databáze: | OpenAIRE |
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