105519-02-6Relevant 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)
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).
On the Use of N-amino Ethers as Capped Azomethine Ylide Equivalents
Padwa, Albert,Dent, William
, p. 235 - 244 (2007/10/02)
N-amino ethers have been found to act as azomethine ylide equivalents.Treatment of these compounds with lithium fluoride in the presence of a reactive dipolarophile afforded dipolar cycloadducts in high yield.The cycloaddition proceeded with complete stereospecificity with dimethyl fumarate and maleate.This result is consistent with the intermediacy of an azomethine ylide.The reaction of N-benzyl-N-(methoxymethyl)-N-amine afforded several silylated diamines when treated with zinc chloride or cesium fluoride in the absence of trapping agent.This can be attributed to an initial loss of the methoxy group to give a transient iminium ion.This species reacts further with the azomethine ylide or undergoes hydrolysis to give a silylated amine.The cycloaddition behavior of several unsymmetrically substituted azomethine ylide precursors was also examined.Competitive rate studies showed that the cycloaddition is compatible with a HOMO-controlled process.The regiochemistry of the cycloaddition, however, is not easily rationalized by simple FMO considerations and may instead be related to the charge transfer interaction energy of the reaction.
