55234-64-5Relevant articles and documents
The Discovery and Hit-to-Lead Optimization of Tricyclic Sulfonamides as Potent and Efficacious Potentiators of Glycine Receptors
Bregman, Howard,Simard, Jeffrey R.,Andrews, Kristin L.,Ayube, Shawn,Chen, Hao,Gunaydin, Hakan,Guzman-Perez, Angel,Hu, Jiali,Huang, Liyue,Huang, Xin,Krolikowski, Paul H.,Lehto, Sonya G.,Lewis, Richard T.,Michelsen, Klaus,Pegman, Pamela,Plant, Matthew H.,Shaffer, Paul L.,Teffera, Yohannes,Yi, Shuyan,Zhang, Maosheng,Gingras, Jacinthe,DiMauro, Erin F.
, p. 1105 - 1125 (2017/02/19)
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).
