Emerging Pharmacotherapies in Alcohol-Associated Hepatitis

Wakil, Ali; Niazi, Mumtaz; Meybodi, Mohamad Aghaie; Pyrsopoulos, Nikolaos

doi:10.1016/j.jceh.2022.06.012

Cited by 13 publications

(37 citation statements)

References 106 publications

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“…2D NOESY NMR (400 MHz, CDCl 3 , ppm) showed a cross peak from N 1 -CH (δ 5.54) to the pyridine ring's H (δ 7.24). 13 Continued elution (eluent: EA/hexane, 1:10, R f = 0.2) provided N 2 -compound M9h as a white solid (18% yield). 1 H NMR (400 MHz, CDCl 3 , ppm) δ 8.57 (s, 1H), 7.58 (s, 1H), 7.45 (dd, J = 11.6, 3.7 Hz, 3H), 7.03 (d, J = 7.5 Hz, 1H), 3.91 (s, 3H).…”

Section: 6-dichloro-1-(pyridin-3-ylmethyl)-1h-pyrazolo[43-c]pyridine ...mentioning

confidence: 99%

“…1 H NMR (400 MHz, CDCl 3 , ppm) δ 8.02 (s, 1H), 6.92 (s, 1H), 4.54 (q, J = 7.2 Hz, 2H), 4.23 (d, J = 7.6 Hz, 2H), 3.99−3.87 (m, 1H), 3.78−3.70 (m, 2H), 3.60 (dd, J = 9.2, 4.8 Hz, 1H), 2.90 (p, J = 6.4 Hz, 1H), 2.01 (dt, J = 13.2, 6.8 Hz, 1H), 1.67 (dq, J = 13.4, 6.8 Hz, 1H), 1.45 (t, J = 7.2 Hz, 3H). 13…”

Section: -Chloro-4-ethoxy-1-((tetrahydrofuran-3-yl)methyl)-1hpyrazolo...mentioning

confidence: 99%

“…1 H NMR (400 MHz, CDCl 3 , ppm) δ 8.55 (s, 2H), 8.08 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.26−7.22 (m, 1H), 6.87 (s, 1H), 5.48 (s, 2H), 4.54 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). 13…”

Section: -Chloro-4-ethoxy-1-(pyridin-3-ylmethyl)-1h-pyrazolo[43-c]pyr...mentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSO-d 6 , ppm) δ 8.63 (s, 1H), 7.20 (s, 1H), 4.59 (t, J = 6.8 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H). 13 General Procedures for the Synthesis of ZL44−ZL49. To a solution of ZL38−ZL43 (1.0 mmol), EDCI (1.5 mmol), and HOBt (1.5 mmol) in DMF (1.5 mL) was added o-(tetrahydro-2H-pyran-2yl)hydroxylamine (1.5 mmol) and DIPEA (3.0 mmol).…”

Section: -(6-chloro-4-ethoxy-2h-pyrazolo[43-c]pyridin-2-yl)propanoic ...mentioning

confidence: 99%

“…10,11 Given these circumstances, there is a critical need to develop novel, safer, and more effective therapeutic drugs for the treatment of both AUD and ALD. 12,13 Phosphodiesterases (PDEs), a class of regulatory hydrolase enzymes, centrally modulate cellular levels of the key second messenger molecules, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP). Phosphodiesterase-4 (PDE4), a specific cAMP hydrolase, has been reported to be a target for various inflammatory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis.…”

Section: ■ Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases

Zheng,

Aimaiti,

Long

et al. 2023

J. Med. Chem.

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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 (IC 50 = 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.

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Section: 6-dichloro-1-(pyridin-3-ylmethyl)-1h-pyrazolo[43-c]pyridine ...mentioning

confidence: 99%

Section: -Chloro-4-ethoxy-1-((tetrahydrofuran-3-yl)methyl)-1hpyrazolo...mentioning

confidence: 99%

Section: -Chloro-4-ethoxy-1-(pyridin-3-ylmethyl)-1h-pyrazolo[43-c]pyr...mentioning

confidence: 99%

Section: -(6-chloro-4-ethoxy-2h-pyrazolo[43-c]pyridin-2-yl)propanoic ...mentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases

Zheng,

Aimaiti,

Long

et al. 2023

J. Med. Chem.

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show abstract

Extraction of edible DNA from Alaska pollock sperm and its preventative effects on alcohol-induced liver injury

Meng,

Xue,

Zhang

et al. 2024

Food Measure

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Roles and correlations of TIM-3 and LAG-3 with cytokines and chemokines in alcoholic liver disease

Fadriquela

Kim

Lee

2023

Clinica Chimica Acta

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Emerging Pharmacotherapies in Alcohol-Associated Hepatitis

Cited by 13 publications

References 106 publications

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases

Extraction of edible DNA from Alaska pollock sperm and its preventative effects on alcohol-induced liver injury

Roles and correlations of TIM-3 and LAG-3 with cytokines and chemokines in alcoholic liver disease

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