Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis

Wu, Yinuo; Wang, Quan; Jiang, Meiyan; Huang, Yi‐You; Zhu, Ziran; Han, Chuan Hsiao; Tian, Yi-Jing; Zhang, Bei; Luo, Hai‐Bin

doi:10.1021/acs.jmedchem.1c00862

Cited by 10 publications

(5 citation statements)

References 32 publications

(63 reference statements)

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“…A more recent study showed that overexpression of PDE4D in the liver led to the development of NAFLD and hypertension in mice, which was attenuated by PDE4 inhibitor treatment [60]. Beyond PDE4, recent papers have shown a role of PDE9 and 10 in liver and lung fibrosis as well as diet-induced obesity [61][62][63][64]. Our data show a significant upregulation of PDE9A and 10A in the livers of AH patients (Figure 5).…”

Section: Discussionsupporting

confidence: 59%

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

Montoya-Durango,

Walter,

Rodriguez

et al. 2023

Biology

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Background: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol. Although the role of cyclic nucleotide signaling is strongly implicated in several pathological pathways in liver diseases, studies describing the changes in genes regulating cyclic nucleotide metabolism in ALD are lacking. Methods: Male C57B/6 mice were used in an intragastric model of alcohol-associated steatohepatitis (ASH). Liver injury, inflammation, and fibrogenesis were evaluated by measuring plasma levels of injury markers, liver tissue cytokines, and gene expression analyses. Liver transcriptome analysis was performed to examine the effects of alcohol on regulators of cyclic AMP and GMP levels and signaling. cAMP and cGMP levels were measured in mouse livers as well as in livers from healthy human donors and patients with alcohol-associated hepatitis (AH). Results: Our results show significant changes in several phosphodiesterases (PDEs) with specificity to degrade cAMP (Pde4a, Pde4d, and Pde8a) and cGMP (Pde5a, Pde6d, and Pde9a), as well as dual-specificity PDEs (Pde1a and Pde10a) in ASH mouse livers. Adenylyl cyclases (ACs) 7 and 9, which are responsible for cAMP generation, were also affected by alcohol. Importantly, adenosine receptor 1, which has been implicated in the pathogenesis of liver diseases, was significantly increased by alcohol. Adrenoceptors 1 and 3 (Adrb), which couple with stimulatory G protein to regulate cAMP and cGMP signaling, were significantly decreased. Additionally, beta arrestin 2, which interacts with cAMP-specific PDE4D to desensitize G-protein-coupled receptor to generate cAMP, was significantly increased by alcohol. Notably, we observed that cAMP levels are much higher than cGMP levels in the livers of humans and mice; however, alcohol affected them differently. Specifically, cGMP levels were higher in patients with AH and ASH mice livers compared with controls. As expected, these changes in liver cyclic nucleotide signaling were associated with increased inflammation, steatosis, apoptosis, and fibrogenesis. Conclusions: These data strongly implicate dysregulated cAMP and cGMP signaling in the pathogenesis of ASH. Future studies to identify changes in these regulators in a cell-specific manner could lead to the development of novel targeted therapies for ASH.

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Section: Discussionsupporting

confidence: 59%

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

Montoya-Durango,

Walter,

Rodriguez

et al. 2023

Biology

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“…AutoMD, a MD-based virtual screening approach 26 , was applied in the present study. AutoMD includes the establishment of pharmacophore model, molecular docking and dynamics simulations, and free energy prediction.…”

Section: Methodsmentioning

confidence: 99%

A novel inhibitor of N6-methyladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities

Xie

Ling

et al. 2022

Acta Pharmaceutica Sinica B

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“…Elevated levels of cAMP and/or cGMP have been found to have antifibrotic effects by inhibiting the myofibroblast-driven ECM production. − Thus, several PDE inhibitors have been used to investigate the antifibrotic effects in different liver fibrosis animal models. For example, the PDE5 inhibitor tadalafil could improve portal hypertension and reduce liver fibrosis induced by bile duct ligation (BDL) in rats. , The PDE3 inhibitor cilostazol could protect rats from alcohol-induced liver fibrosis by suppressing the TGF-β/CTGF activation and the cAMP/EPAC1 signal. , Our group developed a PDE9 inhibitor 4a , which showed significant antifibrotic effects in a BDL-induced rat model …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis

Zhao,

Jiang,

Huang

et al. 2024

J. Med. Chem.

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Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/ 1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC 50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.

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Discovery of Potent Phosphodiesterase-9 Inhibitors for the Treatment of Hepatic Fibrosis

Cited by 10 publications

References 32 publications

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

A novel inhibitor of N6-methyladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis

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