Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues

Roselli, Mariagrazia; Carocci, Alessia; Budriesi, Roberta; Micucci, Matteo; Toma, Maddalena; Mannelli, Lorenzo Di Cesare; Lovece, Angelo; Catalano, Alessia; Cavalluzzi, Maria Maddalena; Bruno, Claudio; Palma, Annalisa De; Contino, Marialessandra; Perrone, Maria Grazia; Colabufo, Nicola Antonio; Chiarini, Alberto; Franchini, Carlo; Ghelardini, Carla; Habtemariam, Solomon; Lentini, Giovanni

doi:10.1016/j.ejmech.2016.05.046

Cited by 19 publications

(20 citation statements)

References 33 publications

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“…In addition, the use of mexiletine is characterized by several drawbacks including epigastric discomfort, atrioventricular heart block, and CNS disturbances. Hence, it has now been discontinued in many countries including the US and the UK (Suetterlin et al, 2015 ; Roselli et al, 2016 ). Consequently, numerous attempts have been made in recent years to develop an alternative to mexiletine, including the design of new analogs that offer the same pharmacological effect but without the unwanted side effects (Roselli et al, 2016 ; De Bellis et al, 2017b ).…”

Section: Discussionmentioning

confidence: 99%

“…Hence, it has now been discontinued in many countries including the US and the UK (Suetterlin et al, 2015 ; Roselli et al, 2016 ). Consequently, numerous attempts have been made in recent years to develop an alternative to mexiletine, including the design of new analogs that offer the same pharmacological effect but without the unwanted side effects (Roselli et al, 2016 ; De Bellis et al, 2017b ). In fact, in a series of our previous structure-activity relationship studies (SAR), we have tested a number of rationally-designed mexiletine derivatives in the attempt to increase potency and use-dependent behavior.…”

Section: Discussionmentioning

confidence: 99%

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Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential

et al. 2018

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Mexiletine (Mex) has been recently appointed as an orphan-drug in myotonic-syndromes, being a potent use-dependent blocker of skeletal-muscle sodium channels (NaV1.4). Available evidences about a potential anti-oxidant effect of Mex and its tetramethyl-pyrroline-derivatives in vivo, suggest the possibility to further enlarge the therapeutic potential of Mex-like compounds in myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative stress. In line with this and based on our previous structure-activity-relationship studies, we synthesized new compounds with a tetramethyl-pyrroline-ring on the amino-group of both Mex (VM11) and of its potent use-dependent isopropyl-derivative (CI16). The compounds were tested for their ability to block native NaV1.4 and to exert cyto-protective effects against oxidative-stress injury in myoblasts. Voltage-clamp-recordings on adult myofibers were performed to assess the tonic and use-dependent block of peak sodium-currents (INa) by VM11 and CI16, as well as Mex, VM11 and CI16 were 3 and 6-fold more potent than Mex in producing a tonic-block of peak sodium-currents (INa), respectively. Interestingly, CI16 showed a 40-fold increase of potency with respect to Mex during high-frequency stimulation (10-Hz), resulting the strongest use-dependent Mex-like compound so far. The derivatives also behaved as inactivated channel blockers, however the voltage dependent block was modest. The experimental data fitted with the molecular-modeling simulation based on previously proposed interaction of main pharmacophores with NaV1.4 binding-site. CI16 and VM11 were then compared to Mex and its isopropyl derivative (Me5) for the ability to protect C2C12-cells from H2O2-cytotoxicity in the concentration range effective on Nav1.4. Mex and Me5 showed a moderate cyto-protective effect in the presence of H2O2, Importantly, CI16 and VM11 showed a remarkable cyto-protection at concentrations effective for use-dependent block of NaV1.4. This effect was comparable to that of selected anti-oxidant drugs proved to exert protective effect in preclinical models of progressive myopathies such as muscular dystrophies. Then, the tetramethyl-pyrroline compounds have increased therapeutic profile as sodium channel blockers and an interesting cyto-protective activity. The overall profile enlarges therapeutic potential from channelopathies to myopathies in which alteration of excitation-contraction coupling is paralleled by oxidative-stress, i.e., muscular dystrophies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential

et al. 2018

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“…These analogues have higher selectivity of action and fewer side effects. 26 As the new drug development cost is increasing and there is still need for newer analgesics for effective treatment of pain, these newer analogues can be considered for evaluation as analgesic agents. There is a need to compare the analgesic potential and tolerability of these analogues in various pain models in animals.…”

Section: Discussionmentioning

confidence: 99%

Dose-dependent analgesic activity of mexiletine on thermally induced pain in rats

Patil¹,

Konda

2018

Int J Basic Clin Pharmacol

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Background: Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. In spite of many advances in pain research, we are unable to deal in an effective way. The cost for new drug development is increasing day by day. Drug repurposing is an approach to look for new use in drugs that are already approved for other indications. Mexiletine is a sodium channel blockers that is being approved for treatment of arrhythmias. It is being tried in treatment of various painful conditions. The present study is to evaluate the dose-dependent analgesic activity of mexiletine with ibuprofen.Methods: The analgesic activity of mexiletine was compared at doses of 15mg/kg, 30mg/kg and 45mg/kg with the standard dose of ibuprofen at 10mg/kg in male Wistar rats in thermal model of tail flick analgesiometer.Results: At lower doses (15mg/kg) of mexiletine, analgesic activity of ibuprofen was significantly higher. At higher doses (30 mg/kg and 45 mg/kg) of mexiletine, it was observed that there is no significant difference between the analgesic activities of both drugs.Conclusions: Mexiletine demonstrated a dose-dependent analgesic activity. There was no statistically significant difference between the analgesic activities of higher doses of mexiletine when compared to ibuprofen.

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“…Additionally, there are rabbit models for dyslipidemia, heart failure, and transgenic rabbits (104, 107, 108). Guinea pigs are not so commonly used for the study of CVD, mainly to study arrhythmias and cellular electrophysiology, e.g., with isolated hearts (109, 110). Furthermore, guinea pig models of cardiac hypertrophy and heart failure exist (111).…”

Section: Methodology – Epidemiological Studies and Experimental Settingsmentioning

confidence: 99%

Systems Medicine as an Emerging Tool for Cardiovascular Genetics

Haase

Börnigen

Müller

et al. 2016

Front. Cardiovasc. Med.

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Cardiovascular disease (CVD) is a major contributor to morbidity and mortality worldwide. However, the pathogenesis of CVD is complex and remains elusive. Within the last years, systems medicine has emerged as a novel tool to study the complex genetic, molecular, and physiological interactions leading to diseases. In this review, we provide an overview about the current approaches for systems medicine in CVD. They include bioinformatical and experimental tools such as cell and animal models, omics technologies, network, and pathway analyses. Additionally, we discuss challenges and current literature examples where systems medicine has been successfully applied for the study of CVD.

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Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues

Cited by 19 publications

References 33 publications

Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential

Dual Action of Mexiletine and Its Pyrroline Derivatives as Skeletal Muscle Sodium Channel Blockers and Anti-oxidant Compounds: Toward Novel Therapeutic Potential

Dose-dependent analgesic activity of mexiletine on thermally induced pain in rats

Systems Medicine as an Emerging Tool for Cardiovascular Genetics

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