Pharmacokinetic characterization of lw6, a novel hypoxia-inducible factor-1α (Hif-1α) inhibitor in mice

Ji Yoon Lee, Kiho Lee, Kyeong Lee, Jong Soon Kang, Min Ju Kim, Dong Gu Yoo, Jung Ah Kim, Eun Jin Shin, Soo Jin Oh

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

LW6, an (aryloxyacetylamino)benzoic acid derivative, was recently identified to be an inhibitor of hypoxia-inducible factor-1α (HIF-1α), which is an attractive target for cancer therapeutics. Although LW6 is known to act by inhibiting the accumulation of HIF-1α, pharmacokinetics needs to be evaluated to assess its potential as an anti-tumor agent. Here, we investigated the plasma pharmacokinetics and metabolism of LW6 in mice. LW6 exhibited a small volume of distribution (0.5 ± 0.1 L/kg), and a short terminal half-life (0.6 ± 0.1 h). Following intravenous or oral admin-istration, LW6 was rapidly converted to its active metabolite, (4-adamantan-1-yl-phenoxy)acetic acid (APA). Although LW6 was rapidly absorbed, its oral bioavailability, estimated using AUClast values, was low (1.7 ± 1.8%). It was slowly degraded in mouse liver microsomes (t1/2 > 1 h) and serum (t1/2 > 6 h). About 54% or 44.8% of LW6 was available systemically as APA in the mouse after a single intravenous or oral administration, respectively. Thus, our results indicated the need to simultaneously consider the active metabolite as well as the parent compound for successful evaluation during lead optimization.

Original languageEnglish
Article number2226
JournalMolecules
Volume26
Issue number8
DOIs
StatePublished - 2 Apr 2021

Keywords

  • Caco-2 cells
  • Liver microsomes
  • LW6
  • Metabolism
  • Mice pharmacokinetics

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