19514-01-3Relevant articles and documents
Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes
Cashman, John R.,Ryan, Daniel,McKeithan, Wesley L.,Okolotowicz, Karl,Gomez-Galeno, Jorge,Johnson, Mark,Sampson, Kevin J.,Kass, Robert S.,Pezhouman, Arash,Karagueuzian, Hrayr S.,Mercola, Mark
, p. 5384 - 5403 (2021/05/29)
Ventricular cardiac arrhythmia (VA) arises in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a congenital form of VA caused by cardiac sodium channel (INaL) SCN5A mutations that prolongs cardiac action potential (AP) and enhances INaL current. Mexiletine inhibits INaL and shortens the QT interval in LQT3 patients. Above therapeutic doses, mexiletine prolongs the cardiac AP. We explored structure-activity relationships (SAR) for AP shortening and prolongation using dynamic medicinal chemistry and AP kinetics in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using patient-derived LQT3 and healthy hiPSC-CMs, we resolved distinct SAR for AP shortening and prolongation effects in mexiletine analogues and synthesized new analogues with enhanced potency and selectivity for INaL. This resulted in compounds with decreased AP prolongation effects, increased metabolic stability, increased INaL selectivity, and decreased avidity for the potassium channel. This study highlights using hiPSC-CMs to guide medicinal chemistry and "drug development in a dish".
Lewis-acid-mediated intramolecular trifluoromethylthiolation of alkenes with phenols: Access to SCF3-containing chromane and dihydrobenzofuran compounds
Song, Xu-Feng,Ding, Tong-Mei,Zhu, Deng,Huang, Jie,Chen, Zhi-Min
supporting information, p. 7052 - 7056 (2020/09/15)
A Lewis-acid-mediated intramolecular trifluoromethylthiolation of alkenes with phenols that can offer direct access to SCF3-containing chromane and dihydrobenzofuran compounds was disclosed for the first time. Numerous SCF3-containing chromanes were obtai
Novel one-pot synthesis of 3-Phenylnaphtho[2,3-b]furan and 3-phenylbenzofurans under microwave irradiation and solvent-free conditions
Wang, Zhongxing,Gu, Jinzhong,Jing, Huanwang,Liang, Yongmin
experimental part, p. 4079 - 4087 (2009/12/24)
A one-pot synthesis of functionalized benzofurans has been developed via O-alkylation, carbon-carbon coupling/cyclization, and dehydration/olefination tandem reactions from phenacyl bromide and phenols under microwave irradiation and solvent-free conditio