Phosphodiesters as GPR84 Antagonists for the Treatment of Ulcerative Colitis

Chen, Linhai; Zhang, Qing; Xiao, Yonglong; Fang, You‐Chen; Xie, Xin

doi:10.1021/acs.jmedchem.1c01813

Cited by 15 publications

(23 citation statements)

References 41 publications

(139 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The organics were concentrated and then purified by preparative HPLC (acidic conditions) to give the title compound 21 (37 mg, 15%). 1 (22). Prepared according to method D. The reaction mixture was evaporated to dryness and then partitioned between water and DCM and passed through a hydrophobic frit.…”

Section: -Imidazo[12-a]pyridin-3-ylacetohydrazide (20a)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Recently, Chen et al published a series of phosphodiester GPR84 antagonists and showed the ability of an exemplar molecule (XIII) to inhibit the chemotaxis of mouse neutrophils and macrophages upon GPR84 activation. 22 Better understanding of the pathophysiological roles of GPR84, and its potential as a therapeutic target in a range of conditions would be enhanced by the availability of a wider range of receptor antagonists. Therefore, there is currently a need to identify new ligands for GPR84 that can be used as chemical probes or lead compounds for drug development.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Investigating the Structure–Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists

et al. 2022

View full text Add to dashboard Cite

G-protein-coupled receptor 84 (GPR84) is a proinflammatory orphan G-protein-coupled receptor implicated in several inflammatory and fibrotic diseases. Several agonist and antagonist ligands have been developed that target GPR84; however, a noncompetitive receptor blocker that was progressed to phase II clinical trials failed to demonstrate efficacy. New high-quality antagonists are required to investigate the pathophysiological role of GPR84 and to validate GPR84 as a therapeutic target. We previously reported the discovery of a novel triazine GPR84 competitive antagonist 1 . Here, we describe an extensive structure–activity relationship (SAR) of antagonist 1 and also present in silico docking with supporting mutagenesis studies that reveals a potential binding pose for this type of orthosteric antagonist. Lead compound 42 is a potent GPR84 antagonist with a favorable pharmacokinetic (PK) profile suitable for further drug development.

show abstract

Section: -Imidazo[12-a]pyridin-3-ylacetohydrazide (20a)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Investigating the Structure–Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In terms of treatment, studies have found that drugs used to treat IPF, such as pirfenidone, may be useful for intestinal fibrosis, a complication of CD [28][29][30][31]. Furthermore, calemin, integrin, and G protein-coupled receptor 84 may be targets for the treatment of both [30,32,33]. Fat stem/stromal cell and stromal vascular fraction treatment can improve IBD and IBF by reducing inflammation and promoting tissue repair [34].…”

Section: Discussionmentioning

confidence: 99%

Inflammatory bowel disease and risk of idiopathic pulmonary fibrosis: A protocol for systematic review and meta-analysis

et al. 2022

View full text Add to dashboard Cite

Introduction Inflammatory bowel disease is a relapsing chronic gastrointestinal inflammatory disease. Idiopathic pulmonary fibrosis is a rare but serious extraintestinal pulmonary manifestation of inflammatory bowel disease. However, the relationship between these two conditions is unclear. Therefore, this study aims to elucidate this relationship through a systematic review and meta-analysis, focusing on the risk of idiopathic pulmonary fibrosis in patients with inflammatory bowel disease. Methods The systematic review will be outlined according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols and its extension statement for reporting systematic reviews incorporating network meta-analyses of healthcare interventions: checklist and explanations. Original articles published in any language will be searched in the following databases: PubMed, Web of Science, EMBASE, Google Scholar, and Ovid. Observational studies that reveal an association measure between idiopathic pulmonary fibrosis and inflammatory bowel disease will be included (cross sectional, cohort, and case-control trials). Two independent reviewers will be assigned to evaluate study quality using the Newcastle–Ottawa scale for assessing the quality of non-randomized studies in meta-analyses. Sensitivity analyses will be conducted based on the quality of included studies. All relevant studies will be assessed based on the study type, sample size, inflammatory bowel disease subtype, odds ratio, confidence interval, treatment strategy, and follow-up. The Grading of Recommendations Assessment, Development, and Evaluation approach will be used to rate the quality of the evidence. Discussion The results of this meta-analysis may show that patients with inflammatory bowel disease are at higher risk of developing idiopathic pulmonary fibrosis. This study will be the first meta-analysis to focus on the association between inflammatory bowel disease and idiopathic pulmonary fibrosis. Exploring the relationship between the two conditions may further enhance our understanding of the pathogenesis of inflammatory bowel disease and idiopathic pulmonary fibrosis and promote the development of related research fields.

show abstract

“…These autoimmune diseases responsible genes might be critical for the development of CD. Recently, study found that CXCL5 [454], S100A12 [455], OSM (oncostatin M) [456], LRG1 [457], LCN2 [458], CXCL1 [459], S100A9 [460], IFITM1 [461], XBP1 [462], MMP3 [457], IFITM3 [463], IL1B [464], GBP5 [465], HGF (hepatocyte growth factor) [466], CXCL9 [467], SLC11A1 [468], IL1RN [469], STAT1 [470], CYP27B1 [471], MMP1 [472], SOCS3 [473], TLR8 [474], CD55 [475], CCL28 [476], FCGR2A [477], CCL2 [478], CFB (complement factor B) [479], CD14 [480], GPR84 [481], PCSK9 [482], FOXP3 [483], LPL (lipoprotein lipase) [484], IL1R2 [485], TLR2 [486], MEFV (MEFV innate immuity regulator, pyrin) [487], VWF (von Willebrand factor) [488], NOD2 [489], DMBT1 [490], HSPA6 [491], TIMP1 [492], ICAM1 [493], EGR1 [494], CCL11 [495], IFNG (interferon gamma) [496], APOE (apolipoprotein E) [497] FGR (FGR proto-oncogene, Src family tyrosine kinase) [498], IL6 [499], SPP1 [192], IL11 [500], RNF186 [501], MMP2 [502], CD24 [503], SPHK1 [504], GZMB (granzyme B) [505], MUC5AC [506], SERPINA3 [507], TWIST1 [508], PLAU (plasminogen activator, urokinase) [509], CA2 [510], CA9 [510], CTLA4 [511], PADI4 [512], MMP13 [513], MPO (myeloperoxidase) [244], LEFTY1 [514], CA1 [515], MMP7 [513], ABCG2 [516], CYP2J2 [517], AICDA (activation induced cytidine deaminase) [518], CYP2D6 [519], CYP3A5 [52...…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

Vastrad¹,

Vastrad²

2022

Preprint

View full text Add to dashboard Cite

Pediatric Crohn's Disease (CD) also known as inflammatory bowel diseases, affects millions of people all over the world. The aim of this investigation is to identify the key genes in CD and uncover their potential functions. We downloaded the next generation sequencing (NGS) dataset GSE73374 from the Gene Expression Omnibus (GEO) database. The NGS dataset GSE73374 was used to screen differentially expressed genes (DEGs) between samples from patients with CD and healthy controls. Gene ontology (GO) and REACTOME pathway enrichment analyses were applied for the DEGs. Subsequently, a protein - protein interaction (PPI) network, modules, miRNA- hub gene regulatory network and TF - hub gene regulatory network were constructed to identify hub genes, miRNAs and TFs. Receiver operating characteristic curve (ROC) analysis was applied to validate the hub genes. A total of 957 DEGs were identified, including 478 up regulated genes and 479 down regulated genes. GO and REACTOME results suggested that several Go terms and pathways are involved in response to stimulus, extracellular region, signaling receptor binding, small molecule metabolic process, membrane, transporter activity, immune system and biological oxidations. The top centrality hub genes MDFI, MNDA, FBXO6, TFRC, STAT1, DPP4, MME, SLC39A4, APOA1 and TMEM25 were screened out as the critical genes among the DEGs from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. This investigation identified key genes and signal pathways, which might help us improve our understanding of the molecular mechanisms of CD and identify some novel therapeutic targets for CD.

show abstract

Phosphodiesters as GPR84 Antagonists for the Treatment of Ulcerative Colitis

Cited by 15 publications

References 41 publications

Investigating the Structure–Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists

Investigating the Structure–Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists

Inflammatory bowel disease and risk of idiopathic pulmonary fibrosis: A protocol for systematic review and meta-analysis

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

Contact Info

Product

Resources

About