5370-01-4Relevant 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".
Production method of mexiletine hydrochloride
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, (2018/04/02)
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
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
, p. 300 - 307 (2016/07/06)
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.
