53012-41-2

Usage

Chemical Properties

Yellow Oil

Uses

Mexiletine (M340800) metabolite.

InChI:InChI=1/C11H14O2/c1-8-5-4-6-9(2)11(8)13-7-10(3)12/h4-6H,7H2,1-3H3

Upstream product

• 16081-16-6 sodium 2,6-dimethylphenolate 
• 598-31-2 1-bromoacetone 
• 31828-71-4 RS-mexiletine 
• 15261-41-3 1-allyloxy-2,6-dimethylbenzene 
• 94991-72-7 (S)-mexiletine 
• 576-26-1 2.6-dimethylphenol 
• 21078-03-5 1,3-dimethyl-2-(prop-2-yn-1-yloxy)benzene 
• 78-95-5 chloroacetone 
• 5370-01-4 (rac)-mexiletine hydrochloride 

Downstream Products

• 1051392-53-0 (E)-1-(2,6-dimethyl-phenoxy)-propan-2-one oxime 
• 31828-71-4 RS-mexiletine 
• 31828-71-4 (R)-mexiletine 
• 61102-09-8 (RS)-1-(2,6-dimethylphenoxy)propan-2-ol 
• 81771-86-0 (2R)-1-(2',6'-dimethylphenoxy)-2-aminopropane hydrochloride 
• 81771-85-9 (+)-Mexiletine hydrochloride 
• 5370-01-4 (rac)-mexiletine hydrochloride 
• 128942-28-9 1-(2,6-dimethylphenoxy)-N-methylpropan-2-amine 
• 194027-20-8 1-(2,6-dimethylphenoxy)-N-ethylpropan-2-amine 

Relevant academic research and scientific papers

Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m-hydroxymexiletine

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.

Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes

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".

Human iPSC-derived cardiomyocytes and pyridyl-phenyl mexiletine analogs

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.

Method for synthesizing mexiletine chloride

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.

Synthetic method for antiarrhythmic drug intermediate 1-(2,6-dimethoxy)-2-propanone

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.

Production method of mexiletine hydrochloride

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.

Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues

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.

Expanding Substrate Specificity of ω-Transaminase by Rational Remodeling of a Large Substrate-Binding Pocket

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.

Primary amines by transfer hydrogenative reductive amination of ketones by using cyclometalated IrIII catalysts

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

Greening the Wacker process

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.