- Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes
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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".
- 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
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p. 5384 - 5403
(2021/05/29)
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- GC–MS study of thermochemical conversion of guaifenesin in the presence of 1-butyl-3-methylimidazolium-based ionic liquids
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Thermochemical conversion of guaifenesin was performed in the presence of 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4] ionic liquid at 80?°C within 2?h. After evaluating the effect of different parameters, such as protic and nonpro
- Hamid, Sharifah Bee Abd,Khaligh, Nader Ghaffari,Sharifi, Mahdieh,Johari, Suzaimi
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p. 4007 - 4021
(2017/06/20)
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- Design, synthesis and effect of the introduction of a propargyloxy group on the fungicidal activities of 1-substituted phenoxypropan-2-amino valinamide carbamate derivatives
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The cell walls of oomycetes are composed of cellulose, making cellulose synthase enzymes good targets for carboxylic acid amide fungicides. Valinamide carbamates are amino acid fungicides that represent excellent alternatives to conventional synthetic pesticides in terms of their ability to reduce the negative impacts of these compounds on human health and the environment. In a continuation of our research towards the development of new cellulose synthase inhibitors, we have developed a series of "stretched" analogues of iprovalicarb by the introduction of an additional OCH2 linker. The bioassay results indicated that compounds containing a small group at the para-position of phenyl gave excellent fungicidal activities with EC50 values ranging from 0.59 to 2.06 μmol L-1. Most notably, the introduction of a propargyloxy group led to a pronounced increase in the fungicidal activity. Furthermore, compound 7o bearing a propargyloxy group was identified as the most promising candidate because of its excellent fungicidal potency against oomycete diseases and good fungicidal activity against non-oomycete diseases.
- Li, Jian-Qiang,Wang, Zhi-Peng,Gao, Yang,Zhao, Wei-Guang
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p. 82131 - 82137
(2016/09/09)
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- Structure-activity relationships in the domain of odorants having marine notes
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Continuing our investigations into marine note odorants, we herein describe several new scaffolds. Among them, 2,3-dihydrobenzofuran-2-carbaldehyde is particularly interesting. The results demonstrate that the seven-membered ring with a ketone functional group of the Calone 1951 family can be replaced by a five-membered ring carrying an aldehydefunction. In addition, this work has allowed us to discover the valuable 2-methoxy-4-methylphenyl methyl carbonate (20b), which is very close to vanillin, and 2-methoxy-2,4-dimethyl-1,3-benzodioxole (29d), which belongs to the isoeugenol/dihydroeugenol olfactive family.
- Gaudin, Jean-Marc,De Saint Laumer, Jean-Yves
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p. 1437 - 1447
(2015/03/04)
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- A photochemical strategy for lignin degradation at room temperature
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The development of a room-temperature lignin degradation strategy consisting of a chemoselective benzylic oxidation with a recyclable oxidant ([4-AcNH-TEMPO]BF4) and a catalytic reductive C-O bond cleavage utilizing the photocatalyst [Ir(ppy)2(dtbbpy)]PF6 is described. This system was tested on relevant lignin model substrates containing β-O-4 linkages to generate fragmentation products in good to excellent yields.
- Nguyen, John D.,Matsuura, Bryan S.,Stephenson, Corey R. J.
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p. 1218 - 1221
(2014/02/14)
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