Discovery, Optimization, and Biological Evaluation of Sulfonamidoacetamides as an Inducer of Axon Regeneration

Axon
regeneration after injury in the central nervous system is
hampered in part because if an age-dependent decline in the intrinsic
axon growth potential, and one of the strategies to stimulate axon
growth in injured neurons involves pharmacological manipulation of
implicated signaling pathways. Here we report phenotypic cell-based
screen of chemical libraries and structure–activity-guided
optimization that resulted in the identification of compound 7p which promotes neurite outgrowth of cultured primary neurons
derived from the hippocampus, cerebral cortex, and retina. In an animal
model of optic nerve injury, compound 7p was shown to
induce growth of GAP-43 positive axons, indicating that the in vitro
neurite outgrowth activity of compound 7p translates
into stimulation of axon regeneration in vivo. Further optimization
of compound 7p and elucidation of the mechanisms by which
it elicits axon regeneration in vivo will provide a rational basis
for future efforts to enhance treatment strategies.