Semapimod (tetrahydrochloride)

Semapimod tetrahydrochloride (CNI-1493), an inhibitor of proinflammatory cytokine production, can inhibit TNF-α, IL-1β, and IL-6. Semapimod tetrahydrochloride inhibits TLR4 signaling (IC₅₀≈0.3 μM). Semapimod tetrahydrochloride inhibits p38 MAPK and nitric oxide production in macrophages. Semapimod tetrahydrochloride has potential in a variety of inflammatory and autoimmune disorders^[1][2][3]. In Vitro:Semapimod tetrahydrochloride leads to a significant decrease of p38-MAPK phosphorylation in macrophages, proinflammatory gene expression of macrophage inflammatory protein-1alpha, interleukin-6, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1, and neutrophil infiltration. Semapimod tetrahydrochloride completely abrogated nitric oxide production within the tunica muscularis^[2].
Semapimod tetrahydrochloride desensitizes TLR signaling via its effect on the TLR chaperone gp96. Semapimod tetrahydrochloride inhibits ATP-binding and ATPase activities of gp96 in vitro (IC₅₀≈0.2-0.4 μM). Semapimod tetrahydrochloride desensitizes TLR signaling via its effect on the TLR chaperone gp96^[3].
Semapimod (0-500 nM) inhibits microglia-stimulated GL261 invasion^[4].
Semapimod (0-10 µM) dose not affect serum-stimulated glioblastoma cell invasion, even at 10 µM, underlining the selectivity of semapimod for cells from the monocytic lineage^[4].
Semapimod (200 nM) does not affect microglia-stimulated glioblastoma cell proliferation^[4].
In Vivo:Semapimod tetrahydrochloride (5 mg/kg; i.p; daily for 2 weeks) ameliorates endothelial dysfunction in Obese Zucker (OZ) rats^[1].
Semapimod tetrahydrochloride restores AM-induced akt phosphorylation and cGMP production in OZ rats^[1].
Semapimod (6 mg/kg/day, Intracranially for 1 week) inhibits glioblastoma cell invasion in vivo^[4].
Semapimod (intracranially administered, 2 weeks) semapimos strongly increases the survival of GL261 tumor-bearing animals in combination with radiation, but has no significant benefit in the absence of radiation^[4].