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

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).