Darapladib is one of the most potent Lp-PLA (Lipoprotein-associated phospholipase A) inhibitor with an IC of 0.25 nM. We demonstrate that a crucial step of Darapladib synthesis was not correctly described in the literature, leading to the production of wrong regioisomers. Moreover we show that the inhibitory activity is directly linked to the position on N1 since compounds bearing alkylation on different sites have potentially less interaction within the active site of Lp-PLA.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2017.12.052 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Predictive and therapeutic value of lipoprotein-associated phospholipaseA2 in sarcopenia in chronic obstructive pulmonary disease.
Int J Biol Macromol
August 2024
National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China. Electronic address:
Background: Sarcopenia, characterized by progressive muscle dysfunction, is a common complication of chronic obstructive pulmonary disease (COPD). Our previous study revealed serum Lipoprotein-associated phospholipaseA2 (Lp-PLA2) level significantly increased in COPD and associated with exercise tolerance. This study further investigated the functions and target potential of Lp-PLA2 for sarcopenia in COPD.
View Article and Find Full Text PDFInhibiting PLA2G7 reverses the immunosuppressive function of intratumoral macrophages and augments immunotherapy response in hepatocellular carcinoma.
J Immunother Cancer
January 2024
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
Background: Hepatocellular carcinoma (HCC) is an exceptionally immunosuppressive malignancy characterized by limited treatment options and a dismal prognosis. Macrophages constitute the primary and heterogeneous immune cell population within the HCC microenvironment. Our objective is to identify distinct subsets of macrophages implicated in the progression of HCC and their resistance to immunotherapy.
View Article and Find Full Text PDFThe lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism.
Nat Commun
September 2023
Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors.
View Article and Find Full Text PDFHuman peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target.
Cell Rep
June 2022
Institut Pasteur, Université de Paris, Malaria Parasite Biology and Vaccines Unit, Paris, France. Electronic address:
The uptake and digestion of host hemoglobin by malaria parasites during blood-stage growth leads to significant oxidative damage of membrane lipids. Repair of lipid peroxidation damage is crucial for parasite survival. Here, we demonstrate that Plasmodium falciparum imports a host antioxidant enzyme, peroxiredoxin 6 (PRDX6), during hemoglobin uptake from the red blood cell cytosol.
View Article and Find Full Text PDFIntegrated analysis of single-cell and bulk RNA sequencing reveals pro-fibrotic PLA2G7 macrophages in pulmonary fibrosis.
Pharmacol Res
August 2022
Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China; Department of Pulmonary and Critical Care Medicine, Chengdu Institute of Respiratory Health, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Chengdu, China. Electronic address:
Pulmonary fibrosis (PF) is the pathological change of end-stage interstitial lung diseases with high mortality and limited therapeutic options. Lung macrophages have distinct subsets with divergent functions, and play critical roles in the pathogenesis of PF. In this study, integrative analysis of lung single-cell and bulk RNA-seq data from patients with fibrotic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis was utilized to identify particular macrophage subsets during the development of PF.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!