90792-95-3Relevant academic research and scientific papers
Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties
Hofmans, Sam,Berghe, Tom Vanden,Devisscher, Lars,Hassannia, Behrouz,Lyssens, Sophie,Joossens, Jurgen,Van Der Veken, Pieter,Vandenabeele, Peter,Augustyns, Koen
, p. 2041 - 2053 (2016/03/22)
Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia reperfusion injury in mice. A chemical inhibitor discovered by high-throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.
Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models
Skouta, Rachid,Dixon, Scott J.,Wang, Jianlin,Dunn, Denise E.,Orman, Marina,Shimada, Kenichi,Rosenberg, Paul A.,Lo, Donald C.,Weinberg, Joel M.,Linkermann, Andreas,Stockwell, Brent R.
supporting information, p. 4551 - 4556 (2014/04/17)
Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes.
Optimization of phenylacetic acid derivatives for CRTH2 and DP selective antagonism
Wang, Yingcai,Fu, Zice,Schmitt, Michael,Wang, Xuemei,Shen, Wang,Rickel, Erika,Martin, Tod,Budelsky, Alison,Marshall, Derek,Collins, Tassie,Tang, H. Lucy,Medina, Julio C.,Liu, Jiwen
scheme or table, p. 367 - 370 (2012/02/16)
We have previously reported that optimization of a series of phenylacetic acid derivatives led to the discovery of CRTH2 and DP dual antagonists, such as AMG 009 and AMG 853. During the optimization process, we discovered that minor structural modifications also afforded potent and selective CRTH2 or DP antagonists. Here we report the structure-activity relationship that led to the discovery of selective CRTH2 antagonists such as 2 and 17, and selective DP antagonists, such as 4 and 5.
Discovery and optimization of CRTH2 and DP dual antagonists
Liu, Jiwen,Fu, Zice,Wang, Yingcai,Schmitt, Mike,Huang, Alan,Marshall, Derek,Tonn, George,Seitz, Lisa,Sullivan, Tim,Lucy Tang,Collins, Tassie,Medina, Julio
scheme or table, p. 6419 - 6423 (2010/05/02)
A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties. These efforts led to selection of AMG 009 as a clinical candidate.
