Compound class:
Synthetic organic
Comment: Compound 1 is reported as a direct inhibitor of the protein-protein interaction between TNFα and both of its receptors (TNFRI and TNFRII) [1]. The compound is orally active, which is in contrast to the TNFα biologics that are already in clinical use e.g. infliximab, adalimumab and etanercept. Compound 1 interacts with TNFα in a two-site binding mode with a high affinity site (nM) and a low affinity site (μM) detected [1]. This mechanism interferes with TNFα homotrimer (bioactive cytokine) formation, and thereby inhibits TNF receptor activation. The physicochemical properties of compound 1 are not optimal (especially wrt solubility), so some medicinal chemistry effort would need to be applied to create a more efficient drug-like molecule.
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Bioactivity Comments |
Compound 1 inhibits TNFα-induced apoptosis of L929 cells and TNFα-induced NF-κB activation in vitro, and protects mice from TNFκ-dependent hepatic shock in vivo. Compound 1 inhibits TNFα binding to TNFRI (TNFRSF1A; ubiquitously expressed) and TNFRII (TNFRSF1B; expression restricted to hematopoietic cells) with comparable affinity (IC50 ~30μM) [1]. |
Selectivity at ligand targets | ||||||||||||||||||||||||||||||||||
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