Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents
Copyright © 2024 Elsevier Masson SAS. All rights reserved..
The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC50 values at the nanomolar level. Impressively, the compound (S)-2a (10 μM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:268 |
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| Enthalten in: |
European journal of medicinal chemistry - 268(2024) vom: 15. März, Seite 116280 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Song, Huijuan [VerfasserIn] |
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| Links: |
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| Themen: |
4B9XT59T7S |
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| Anmerkungen: |
Date Completed 18.03.2024 Date Revised 18.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2024.116280 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369478452 |
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| 245 | 1 | 0 | |a Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC50 values at the nanomolar level. Impressively, the compound (S)-2a (10 μM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Anti- HBV | |
| 650 | 4 | |a HBsAg | |
| 650 | 4 | |a Neurotoxicity | |
| 650 | 4 | |a PAPD5/7 | |
| 650 | 4 | |a RG7834 | |
| 650 | 7 | |a Hepatitis B Surface Antigens |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Zidovudine |2 NLM | |
| 650 | 7 | |a 4B9XT59T7S |2 NLM | |
| 700 | 1 | |a Yang, Shangze |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Shuo |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Xiaoyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ya |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Xican |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Jiaqi |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Apeng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Mengyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, Kun |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Mingliang |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xingjuan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yuhuan |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Kai |e verfasserin |4 aut | |
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