- Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m-hydroxymexiletine
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Mexiletine is a sodium channel blocker, primarily used in the treatment of ventricular arrhythmias. Moreover, recent studies have demonstrated its therapeutic value to treat myotonic syndromes and to relieve neuropathic pain. The present study aims at investigating the direct blockade of hERG potassium channel by mexiletine and its metabolite m-hydroxymexiletine (MHM). Our data show that mexiletine inhibits hERG in a time- and voltage-dependent manner, with an IC50 of 3.7 ± 0.7 lmol/L. Analysis of the initial onset of current inhibition during a depolarizing test pulse indicates mexiletine binds preferentially to the open state of the hERG channel. Looking for a possible mexiletine alternative, we show that m-hydroxymexiletine (MHM), a minor mexiletine metabolite recently reported to be as active as the parent compound in an arrhythmia animal model, is a weaker hERG channel blocker, compared to mexiletine (IC50 = 22.4 ± 1.2 lmol/L). The hERG aromatic residues located in the S6 helix (Tyr652 and Phe656) are crucial in the binding of mexiletine and the different affinities of mexiletine and MHM with hERG channel are interpreted by modeling their corresponding binding interactions through ab initio calculations. The simulations demonstrate that the introduction of a hydroxyl group on the meta-position of the aromatic portion of mexiletine weakens the interaction of the drug xylyloxy moiety with Tyr652. These results provide further insights into the molecular basis of drug/hERG interactions and, in agreement with previously reported results on clofilium and ibutilide analogs, support the possibility of reducing hERG potency and related toxicity by modifying the aromatic pattern of substitution of clinically relevant compounds.
- Gualdani, Roberta,Tadini-Buoninsegni, Francesco,Roselli, Mariagrazia,Defrenza, Ivana,Contino, Marialessandra,Colabufo, Nicola Antonio,Lentini, Giovanni
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Read Online
- 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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- Human iPSC-derived cardiomyocytes and pyridyl-phenyl mexiletine analogs
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In the United States, approximately one million individuals are hospitalized every year for arrhythmias, making arrhythmias one of the top causes of healthcare expenditures. Mexiletine is currently used as an antiarrhythmic drug but has limitations. The purpose of this work was to use normal and Long QT syndrome Type 3 (LQTS3) patient-derived human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to identify an analog of mexiletine with superior drug-like properties. Compared to racemic mexiletine, medicinal chemistry optimization of substituted racemic pyridyl phenyl mexiletine analogs resulted in a more potent sodium channel inhibitor with greater selectivity for the sodium over the potassium channel and for late over peak sodium current.
- Cashman, John R.,Gomez-Galeno, Jorge,Johnson, Mark,Kass, Robert S.,McKeithan, Wesley L.,Mercola, Mark,Okolotowicz, Karl,Ryan, Daniel,Sampson, Kevin J.
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supporting information
(2021/06/15)
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- Method for synthesizing mexiletine chloride
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The invention discloses a method for synthesizing mexiletine chloride, wherein a reaction system takes 2,6-xylenol as a starting material to synthesize a corresponding target product. In the reaction,a transition metal gold complex and a ruthenium complex are used for catalysis, compared with the previous method for synthesizing mexiletine chloride, no alkali is added during a reaction process, no by-products are produced, the reaction atom economy is high, and the reaction conditions are mild. Therefore, the method has broad development prospects.
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Paragraph 0031; 0032; 0033; 0034
(2019/03/15)
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- Synthetic method for antiarrhythmic drug intermediate 1-(2,6-dimethoxy)-2-propanone
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The invention discloses a synthetic method for the antiarrhythmic drug intermediate 1-(2,6-dimethoxy)-2-propanone. The synthetic method comprises the following steps: adding 1-(2,6-dimethyl-3-hydroxy-phenoxy)-2-aminopropane and a potassium nitrate solution into a reaction vessel, controlling a stirring speed, raising a solution temperature, adding a butyl benzyl phthalate solution, and continuinga reaction; and adding vananocene dichloride and a sodium sulfate solution, lowering the temperature, carrying out standing to realize the layering of the solution, separating an oil layer, washing the oil layer with a sulfur hexafluoride solution, then washing the oil layer with a 2-chlorophenol solution, carrying out recrystallization in a methyl chloride solution, and then carrying out dehydration with a dehydrating agent to obtain the finished 1-(2,6-dimethoxy)-2-propanone.
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Paragraph 0013; 0017; 0018; 0021-0026
(2018/07/30)
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- Production method of mexiletine hydrochloride
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The invention provides a production method of mexiletine hydrochloride. The method comprises: a etherification step, namely dissolving 2,6-dimethylphenol in a solid-liquid heterogeneous reaction system to obtain a mixed solution, mixing chloroacetone with the mixed solution, and performing reflux reaction to obtain ether ketone, wherein the solid-liquid heterogeneous reaction system comprises a solvent, a solid-liquid phase transfer promoter, inorganic base and an alkali metal halide; an amination reduction step, namely under suitable reaction conditions, contacting the ether ketone with ammonia methanol to carry out amination reduction reaction to obtain ether amine; and a salting step, namely reacting the ether amine with hydrogen chloride in the solvent to obtain the mexiletine hydrochloride. The method disclosed by the invention improves the reaction efficiency and the production efficiency, and has the advantages of low production cost, small resource consumption and high production efficiency.
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Paragraph 0031; 0041-0053
(2018/04/02)
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- Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues
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Four mexiletine analogues have been tested for their antiarrhythmic, inotropic, and chronotropic effects on isolated Guinea pig heart tissues and to assess calcium antagonist activity, in comparison with the parent compound mexiletine. All analogues showed from moderate to high antiarrhythmic activity. In particular, three of them (1b,c,e) were more active and potent than the reference drug, while exhibiting only modest or no negative inotropic and chronotropic effects and vasorelaxant activity, thus showing high selectivity of action. All compounds showed no cytotoxicity and 1b,c,d did not impair motor coordination. All in, these new analogues exhibit an interesting cardiovascular profile and deserve further investigation.
- Roselli, Mariagrazia,Carocci, Alessia,Budriesi, Roberta,Micucci, Matteo,Toma, Maddalena,Di Cesare Mannelli, Lorenzo,Lovece, Angelo,Catalano, Alessia,Cavalluzzi, Maria Maddalena,Bruno, Claudio,De Palma, Annalisa,Contino, Marialessandra,Perrone, Maria Grazia,Colabufo, Nicola Antonio,Chiarini, Alberto,Franchini, Carlo,Ghelardini, Carla,Habtemariam, Solomon,Lentini, Giovanni
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supporting information
p. 300 - 307
(2016/07/06)
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- Expanding Substrate Specificity of ω-Transaminase by Rational Remodeling of a Large Substrate-Binding Pocket
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Production of structurally diverse chiral amines via biocatalytic transamination is challenged by severe steric interference in a small active site pocket of ω-transaminase (ω-TA). Herein, we demonstrated that structure-guided remodeling of a large pocket by a single point mutation, instead of excavating the small pocket, afforded desirable alleviation of the steric constraint without deteriorating parental activities toward native substrates. Molecular modeling suggested that the L57 residue of the ω-TA from Ochrobactrum anthropi acted as a latch that forced bulky substrates to undergo steric interference with the small pocket. Removal of the latch by a L57A substitution allowed relocation of the small pocket and dramatically improved activities toward various arylalkylamines and alkylamines (e.g., 1100-fold increase in kcat/KM for α-propylbenzylamine). This approach may provide a facile strategy to broaden the substrate specificity of ω-TAs.
- Han, Sang-Woo,Park, Eul-Soo,Dong, Joo-Young,Shin, Jong-Shik
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p. 2712 - 2720
(2015/09/01)
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- Primary amines by transfer hydrogenative reductive amination of ketones by using cyclometalated IrIII catalysts
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Cyclometalated iridium complexes are found to be versatile catalysts for the direct reductive amination (DRA) of carbonyls to give primary amines under transfer-hydrogenation conditions with ammonium formate as both the nitrogen and hydrogen source. These complexes are easy to synthesise and their ligands can be easily tuned. The activity and chemoselectivity of the catalyst towards primary amines is excellent, with a substrate to catalyst ratio (S/C) of 1000 being feasible. Both aromatic and aliphatic primary amines were obtained in high yields. Moreover, a first example of homogeneously catalysed transfer-hydrogenative DRA has been realised for β-keto ethers, leading to the corresponding β-amino ethers. In addition, non-natural α-amino acids could also be obtained in excellent yields with this method. Reduce the work! A broad range of ketones have been successfully aminated to afford primary amines under transfer-hydrogenation conditions by using ammonium formate as the amine source and 0.1 mol % of a cyclometalated IrIII catalyst (see scheme). Copyright
- Talwar, Dinesh,Salguero, Noemi Poyatos,Robertson, Craig M.,Xiao, Jianliang
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p. 245 - 252
(2014/01/17)
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- Greening the Wacker process
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Wacker oxidation of various terminal olefins with Pd0/C- KBrO3, a nontoxic, environmentally benign, and easy to handle catalyst system, was achieved in high isolated yields. The described protocol offers an alternative to the traditional Wacker system which uses CuCl 2 as co-catalyst. The catalyst is reusable while maintaining high activity and selectivity.
- Kulkarni, Mukund G.,Shaikh, Yunnus B.,Borhade, Ajit S.,Chavhan, Sanjay W.,Dhondge, Attrimuni P.,Gaikwad, Dnyaneshwar D.,Desai, Mayur P.,Birhade, Deekshaputra R.,Dhatrak, Nagorao R.
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supporting information
p. 2293 - 2295
(2013/06/26)
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- Deracemisation of α-chiral primary amines by a one-pot, two-step cascade reaction catalysed by ω-transaminases
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Racemic a-chiral primary amines were deracemised to optically pure amines in up to >99 % conversion and >99 % ee within 48 h. The deracemisation was a result of a stereoinver- sion of one amine enantiomer; the formal stereoinversion was achieved by a one-pot, two-step procedure: in the first step, kinetic resolution of the chiral racemic amine was performed by employing a -transaminase to yield an intermediate ketone and the remaining optically pure amine; in the second step, the ketone intermediate was stereoselectively transformed into the amine by employing alanine as the amine donor and a -transaminase displaying opposite stereopref- erence than the -transaminase in the first step. In the second step, lactate dehydrogenase was used to remove the side product pyruvate to shift the unfavourable reaction equilibrium to the product side. Depending on the order of the en- antiocomplementary enzymes employed in the cascade, the (R), as well as the (S), enantiomer was accessible.
- Koszelewski, Dominik,Clay, Dorina,Rozzell, David,Kroutil, Wolfgang
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experimental part
p. 2289 - 2292
(2009/08/09)
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- Deracemization of mexiletine biocatalyzed by ω-transaminases
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(S)- as well as (R)-mexiletine [1-(2,6-dimethylphenoxy)-2-propanamine], a chiral orally effective antiarrhythmic agent, was prepared by deracemizatlon starting from the commercially available racemic amine using ω-transaminases In up to >99% ee and conver
- Koszelewski, Dominik,Pressnitz, Desiree,Clay, Dorina,Kroutil, Wolfgang
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supporting information; experimental part
p. 4810 - 4812
(2010/03/01)
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- A practical and efficient route for the highly enantioselective synthesis of mexiletine analogues and novel β-thiophenoxy and pyridyl ethers
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(Chemical Equation Presented) A practical and efficient procedure for the enantioselective synthesis of mexiletine analogues with use of 10% of spiroborate ester 6 as chirality transfer agent is presented. A variety of mexiletine analogues were prepared in good yield with excellent enantioselectivities (91-97% ee) from readily available starting materials. The developed methodology was also successfully applied for the synthesis of novel β-amino ethers containing thiophenyl and pyridyl fragments.
- Huang, Kun,Ortiz-Marciales, Margarita,Stepanenko, Viatcheslav,De Jesus, Melvin,Correa, Wildeliz
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p. 6928 - 6931
(2008/12/22)
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- Photochemical and chemical oxidation of mexiletine and tocainide. Structure elucidation of the major products
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Mexiletine (mex) and tocainide (toc) are antiarrhythmic drugs of closely related structure. Several degradation products are formed by interaction with both light and oxidizing agents in the case of mex, and only by oxidants with toc. On the basis of the
- Takacs, Mihaly,Vamos, Jozsef,Toth, Gabor,Miko-Hideg, Zsuzsa
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