90792-95-3Relevant articles and documents
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.
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.
