Design, Synthesis, and Antifibrosis Activity in Liver of Nonsecosteroidal Vitamin D Receptor Agonists with Phenyl-pyrrolyl Pentane Skeleton

Wang, Bin; Xue, Lingjing; Kang, Zisheng; Hou, Siyuan; Du, Junjie; Zhang, Can

doi:10.1021/acs.jmedchem.8b01165

Cited by 9 publications

(3 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… However, compared with 1,25(OH) 2 D 3 , the binding affinity and transcriptional activity of LG190178 were modest. Therefore, to find more potential nonsecosteroidal VDR agonists, 225 nonsteroidal 1,25(OH) 2 D 3 analogues using LG190178 as the leading compound were designed, synthetized, and screened in our previous studies. − …”

Section: Resultsmentioning

confidence: 99%

“…In order to discover new VDR agonists without hypercalcemia, our group have designed and characterized a series of nonsecosteroidal VDR agonists that bear a phenyl-pyrrolyl pentane scaffold. − Among them, compounds 11b and 11d (Figure ) showed satisfactory binding affinity and transcriptional activation . However, the structure of these compounds can further be optimized for better activity and application in more refractory indications.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Kang

et al. 2020

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

In a pancreatic tumor microenvironment, activated pancreatic stellate cells (PSCs) produce extracellular matrix (ECM) to form a barrier to drug penetration. Moreover, the interaction between cancer cells and activated PSCs promotes the tumor growth. Vitamin D receptor (VDR), as a key regulator to promote the recovery of PSCs to the resting state, is an attractive therapeutic target for pancreatic cancer. Herein, we reported the design and synthesis of 57 nonsecosteroidal VDR modulators based on the skeleton of phenyl-pyrrolyl pentane. Among them, compounds C4, I5, and I8 exhibited excellent VDR affinity and effective inhibition of the activation of PSCs, as well as potent suppression of the interaction between cancer cells and PSCs in vitro. In vivo, compound I5 combined with gemcitabine achieved efficacious antitumor activity without causing hypercalcemia. In conclusion, the compounds designed in our study can remodel the tumor microenvironment and are expected to be candidates for the treatment of pancreatic cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Kang

et al. 2020

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Currently, the therapeutic concepts for NASH consist of reducing hepatic fat accumulation, relieving oxidative stress and inflammation, and delaying and reversing fibrosis . Many efforts have been made on drug design and discovery to provide solutions. − Some compounds have entered phase III trials, including obeticholic acid (farnesoid X receptor agonist), VK-2809 (thyroid hormone receptor β agonist), GFT-505 (peroxisome proliferator-activated receptor α/δ agonist), cenicriviroc (C–C chemokine receptor type 2/5 antagonist), and GS-4997 (apoptosis signal-regulating kinase 1 inhibitor). , However, none of them has been approved for marketing. Hence, anti-NASH drugs are in urgent clinical needs.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation

Dai

Feng

Zha

et al. 2020

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Nonalcoholic steatohepatitis (NASH) is one of the important causes of cirrhosis and hepatocellular carcinoma worldwide. PPARα is highly expressed in the liver and plays a critical role in hepatic lipid metabolism. Our analysis of the gene expression profiles in the liver of humanized mice treated with a PPARα agonist and NASH patients suggested that PPARα might be a potential target for NASH therapy. This promoted us to find novel PPARα agonists. The results of virtual screening and biological evaluation identified compound A-4 as a selective PPARα agonist. It significantly regulated the target genes of PPARα involved in fatty acid metabolism and inflammation, exhibiting cellular anti-inflammatory activity. The key residues involved in the binding between PPARα ligand-binding domain (LBD) and compound A-4 were revealed by molecular dynamics (MD) simulation and further experimentally validated by the mutation study. Together, compound A-4 was well characterized as a novel lead compound for developing potent and selective PPARα agonists.

show abstract

Design and Synthesis of Dual Galectin‐3 and EGFR Inhibitors Against Liver Fibrosis

Liu,

He,

Jin

et al. 2024

Chemistry An Asian Journal

View full text Add to dashboard Cite

Liver fibrosis, mainly arising from chronic viral or metabolic liver diseases, is a significant global health concern. There is currently only one FDA‐approved drug (Resmetirom) in the market to combat liver fibrosis. Both galectin‐3 and epidermal growth factor receptor (EGFR) play important roles in liver fibrosis, while galectin‐3 may interact with EGFR. Galectin‐3 inhibitors, typically lactose or galactose derivatives may inhibit liver fibrosis. We hypothesized that targeting both galectin‐3 and EGFR may have better effect against liver fibrosis. Here, EGFR inhibitor erlotinib was used in a series of designed galectin‐3 inhibitors after hybridization with the pharmacophore structure in reported galectin‐3 inhibitors to impede hepatic stellate cells (HSCs) activation by a typical method of click chemistry. Bioactivity test results showed that compound 29 suppressed TGF‐β‐induced upregulation of fibrotic markers (α‐SMA, fibronectin‐1, and collagen I). The preferred compound 29 displayed better binding to galectin‐3 (KD = 52.29 μM) and EGFR protein (KD = 3.31 μM) by SPR assay. Further docking studies were performed to clarify the possible binding mode of compound 29 with galectin‐3 and EGFR. Taken together, these results suggested that compound 29 could be a potential dual galectin‐3 and EGFR inhibitor as leading compound for anti‐liver fibrosis new drug development.

show abstract

Design, Synthesis, and Antifibrosis Activity in Liver of Nonsecosteroidal Vitamin D Receptor Agonists with Phenyl-pyrrolyl Pentane Skeleton

Cited by 9 publications

References 40 publications

Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation

Design and Synthesis of Dual Galectin‐3 and EGFR Inhibitors Against Liver Fibrosis

Contact Info

Product

Resources

About