2. Academic Validation
  3. Anti-neuroinflammatory Effects and Brain Pharmacokinetic Properties of Selonsertib, an Apoptosis signal-regulating Kinase 1 Inhibitor, in mice

Anti-neuroinflammatory Effects and Brain Pharmacokinetic Properties of Selonsertib, an Apoptosis signal-regulating Kinase 1 Inhibitor, in mice

  • Neurochem Res. 2022 Oct 30. doi: 10.1007/s11064-022-03777-9.
Ji Hun Lee 1 2 3,  Sang Hee Ji 4 5,  Jong Seung Lim 1,  Sunjoo Ahn 1,  Hwi-Yeol Yun 2,  Seong Hwan Kim 6 7,  Jin Sook Song 8
Affiliations

Affiliations

  • 1 Data Convergence Drug Research Center, Therapeutics & Biotechnology Division, Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, 34114, Daejeon, Korea.
  • 2 College of Pharmacy, Chungnam National University, Daejeon, Korea.
  • 3 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundataion, 41061, Daegu, Korea.
  • 4 Drug Discovery Platform Research Center, Therapeutics & Biotechnology Division, Research Institute of Chemical Technology, 34114, Daejeon, Korea.
  • 5 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea.
  • 6 Drug Discovery Platform Research Center, Therapeutics & Biotechnology Division, Research Institute of Chemical Technology, 34114, Daejeon, Korea. hwan@krict.re.kr.
  • 7 Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea. hwan@krict.re.kr.
  • 8 Data Convergence Drug Research Center, Therapeutics & Biotechnology Division, Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, 34114, Daejeon, Korea. jssong@krict.re.kr.
PMID: 36309631 DOI: 10.1007/s11064-022-03777-9
Abstract

Selonsertib is a first-in-class Apoptosis signal-regulating kinase 1 (ASK1) inhibitor in clinical trials for treating NASH and diabetic kidney disease due to its anti-inflammatory and anti-fibrotic activities. In the present study, we investigated the anti-neuroinflammatory effects and brain pharmacokinetic properties of selonsertib. It inhibited inflammatory cytokines and NO production by suppressing phosphorylated ASK1 in the LPS-stimulated microglial cell line, BV2 cells. Consistent with the in vitro results, selonsertib attenuated plasma and brain TNF-α levels in the LPS-induced murine neuroinflammation model. In vitro and in vivo pharmacokinetic studies of selonsertib were conducted in support of central nervous system (CNS) drug discovery. In both Caco-2 and MDR-MDCK cells, selonsertib exhibited a high efflux ratio, showing that it is a P-gp substrate. Selonsertib was rapidly and effectively absorbed into the systemic circulation after oral treatment, with a Tmax of 0.5 h and oral bioavailability of 74%. In comparison with high systemic exposure with Cmax of 16.2 µg/ml and AUC of 64 µg·h/mL following oral dosing of 10 mg/kg, the brain disposition of selonsertib was limited, with Cmax of 0.08 µg/g and Kp value of 0.004. This study demonstrates that selonsertib can be a therapeutic agent for neuroinflammatory diseases.

Keywords

Apoptosis signal-regulating kinase 1; Central nervous system; Neuroinflammation; Pharmacokinetics; Selonsertib.

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