ICA-105665 (PF-04895162) is a potent and orally active opener of neuronal Kv7.2/7.3 and Kv7.3/7.5 potassium channels. ICA-105665 had low cytotoxic potential in human hepatocytes but inhibited liver mitochondrial function and bile salt export protein (BSEP) transport (IC50 of 311 μM). ICA-105665 can penetrate the central nervous system (CNS) and has antiseizure effects [1][2][3][4].

ICA-105665 (PF-04895162) shows minimal cytotoxic effects in THLE and HepG2 cell lines, with IC 50 values of approximately 192 μM and 130 μM after 72 hours, respectively, and exhibits negligible cell loss in human hepatocytes, with an AC 50 of over 125 μM as determined by three assessments across two hepatocyte batches (LBN and HU4165) [1]. Furthermore, it impairs mitochondrial respiratory capacity in human hepatocytes at concentrations exceeding 11 μM when exposed for 25 minutes [1].

ICA-105665 (PF-04895162) exhibited dose-dependent alanine aminotransferase (ALT) elevations in a 7-day rat toxicity study, suggesting potential liver toxicity. Nonetheless, no histological liver injury was observed, and subsequent 7-day studies did not confirm ALT elevations. Further, both 28-day and 6-month rat studies, as well as up to 9-month toxicity studies in cynomolgus monkeys, showed no transaminase elevations or liver toxicity. Additionally, ICA-105665 (PF-04895162) has shown broad-spectrum antiseizure efficacy across several animal models, including maximal electroshock, 6 Hz seizures, pentylenetetrazole, and electrical kindling, at doses ranging from <1 to 5 mg/kg [3].