Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases
Alcohol use disorder (AUD) results in numerous disabilities and approximately 3 million deaths annually, caused mainly by alcoholic liver disease (ALD). Phosphodiesterase IV (PDE4) has emerged as an attractive molecular target for a new treatment for AUD and ALD. In this study, we describe the identification of 5-azaindazole analogues as PDE4 inhibitors against AUD and ALD. System optimization studies led to the discovery of ZL40 (IC50 = 37.4 nM) with a remarkable oral bioavailability (F = 94%), satisfactory safety, and a lower emetogenic potency than the approved PDE4 inhibitors roflumilast and apremilast. Encouragingly, ZL40 exhibited AUD therapeutic effects by decreasing alcohol intake and improving acute alcohol-induced sedation and motor impairment. Meanwhile, ZL40 displayed the potential to alleviate alcoholic liver injury and attenuate inflammation in the NIAAA mice model. These results showed that ZL40 is a promising compound for future drug development to treat alcohol-related diseases.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 1 vom: 11. Jan., Seite 728-753 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zheng, Lei [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
3K9958V90M |
|---|
| Anmerkungen: |
Date Completed 12.01.2024 Date Revised 12.01.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.jmedchem.3c02087 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM366472682 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366472682 | ||
| 003 | DE-627 | ||
| 005 | 20240114234350.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240108s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.3c02087 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1257.xml |
| 035 | |a (DE-627)NLM366472682 | ||
| 035 | |a (NLM)38156615 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zheng, Lei |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.01.2024 | ||
| 500 | |a Date Revised 12.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Alcohol use disorder (AUD) results in numerous disabilities and approximately 3 million deaths annually, caused mainly by alcoholic liver disease (ALD). Phosphodiesterase IV (PDE4) has emerged as an attractive molecular target for a new treatment for AUD and ALD. In this study, we describe the identification of 5-azaindazole analogues as PDE4 inhibitors against AUD and ALD. System optimization studies led to the discovery of ZL40 (IC50 = 37.4 nM) with a remarkable oral bioavailability (F = 94%), satisfactory safety, and a lower emetogenic potency than the approved PDE4 inhibitors roflumilast and apremilast. Encouragingly, ZL40 exhibited AUD therapeutic effects by decreasing alcohol intake and improving acute alcohol-induced sedation and motor impairment. Meanwhile, ZL40 displayed the potential to alleviate alcoholic liver injury and attenuate inflammation in the NIAAA mice model. These results showed that ZL40 is a promising compound for future drug development to treat alcohol-related diseases | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Phosphodiesterase 4 Inhibitors |2 NLM | |
| 650 | 7 | |a Ethanol |2 NLM | |
| 650 | 7 | |a 3K9958V90M |2 NLM | |
| 700 | 1 | |a Aimaiti, Zulihuma |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Chuang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Wenya |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Zhong-Zhen |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 67(2024), 1 vom: 11. Jan., Seite 728-753 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:67 |g year:2024 |g number:1 |g day:11 |g month:01 |g pages:728-753 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.3c02087 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 67 |j 2024 |e 1 |b 11 |c 01 |h 728-753 | ||