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Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice

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 evaluate...

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Autores principales: Lee, Ji-Yoon, Lee, Kiho, Lee, Kyeong, Kang, Jong Soon, Kim, Min Ju, Yoo, Dong Gu, Kim, Jung Ah, Shin, Eun Jin, Oh, Soo Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070284/
https://www.ncbi.nlm.nih.gov/pubmed/33921487
http://dx.doi.org/10.3390/molecules26082226
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author Lee, Ji-Yoon
Lee, Kiho
Lee, Kyeong
Kang, Jong Soon
Kim, Min Ju
Yoo, Dong Gu
Kim, Jung Ah
Shin, Eun Jin
Oh, Soo Jin
author_facet Lee, Ji-Yoon
Lee, Kiho
Lee, Kyeong
Kang, Jong Soon
Kim, Min Ju
Yoo, Dong Gu
Kim, Jung Ah
Shin, Eun Jin
Oh, Soo Jin
author_sort Lee, Ji-Yoon
collection PubMed
description 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 administration, 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 AUC(last) values, was low (1.7 ± 1.8%). It was slowly degraded in mouse liver microsomes (t(1/2) > 1 h) and serum (t(1/2) > 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.
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spelling pubmed-80702842021-04-26 Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice Lee, Ji-Yoon Lee, Kiho Lee, Kyeong Kang, Jong Soon Kim, Min Ju Yoo, Dong Gu Kim, Jung Ah Shin, Eun Jin Oh, Soo Jin Molecules Article 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 administration, 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 AUC(last) values, was low (1.7 ± 1.8%). It was slowly degraded in mouse liver microsomes (t(1/2) > 1 h) and serum (t(1/2) > 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. MDPI 2021-04-12 /pmc/articles/PMC8070284/ /pubmed/33921487 http://dx.doi.org/10.3390/molecules26082226 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Ji-Yoon
Lee, Kiho
Lee, Kyeong
Kang, Jong Soon
Kim, Min Ju
Yoo, Dong Gu
Kim, Jung Ah
Shin, Eun Jin
Oh, Soo Jin
Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice
title Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice
title_full Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice
title_fullStr Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice
title_full_unstemmed Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice
title_short Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice
title_sort pharmacokinetic characterization of lw6, a novel hypoxia-inducible factor-1α (hif-1α) inhibitor in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070284/
https://www.ncbi.nlm.nih.gov/pubmed/33921487
http://dx.doi.org/10.3390/molecules26082226
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