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

详细信息    查看全文

• 作者：Howard BregmanJeffrey R. Simard ; Kristin L. Andrews ; Shawn Ayube ; Hao Chen ; Hakan Gunaydin ; Angel Guzman-Perez ; Jiali Hu ; Liyue Huang ; Xin Huang ; Paul H. Krolikowski ; Sonya G. Lehto ; Richard T. Lewis ; Klaus Michelsen ; Pamela Pegman ; Matthew H. Plant ; Paul L. Shaffer ; Yohannes Teffera ; Shuyan Yi ; Maosheng Zhang ; Jacinthe Gingras ; Erin F. DiMauro
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：60
• 期：3
• 页码：1105-1125
• 全文大小：937K
• ISSN：1520-4804

文摘

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 GlyRα3_cryst to afford the first described potentiator-bound X-ray cocrystal structure within this class of ligand-gated ion channels (LGICs).