758679-97-9

CID-2858522 (Compound 1) inhibits antigen receptor-mediated NF-κB with an IC ₅₀ of 70 nM. CID-2858522 also inhibits testosterone hydroxylase in the presence of human liver microsomes (HLM) and an NADPH generating system with an IC ₅₀ of 85 μM. In the HEK293 cell line used for primary screening, CID-2858522 suppresses NF-κB reporter gene activity in a concentration-dependent manner, with IC ₅₀ ~70 nM and with maximum inhibition achieved at 0.25-0.5 μM. In contrast, CID-2858522 does not inhibit TNF-induced NF-κB-reporter gene activity at concentrations as high as 4 μM, thus demonstrating selectivity for the NF-κB pathway activated by PMA/Ionomycin. Cell viability assays indicate that CID-2858522 is not toxic to HEK293 cells at concentrations ≤8 μM. CID-2858522 also potently inhibits PMA/Ionomycin-induced NF-κB reporter gene activity in transient transfection assays.

In vivo dose-exposure profiling of CID-2858522 (Compound 1a) is conducted using a small cohort of three male mice. CID-2858522 exhibits nonlinear pharmacokinetics, showing higher serum levels at the 0.5 h measurement time for the 30 mg/kg dose compared to 50 mg/kg but displaying typical dose-dependent behavior when measured at t=3 h. The increasing accumulation seen at a dose of 50 mg/kg may be due to a depot effect created by CYP3A4 inhibition. The cohort exhibits clear signs of morbidity at t=3 h at the 50 mg/kg dose.