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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8070284 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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