2. Academic Validation
  3. Hunting for lubeluzole analogues as antimyotonic agents with reduced cardiac liability

Hunting for lubeluzole analogues as antimyotonic agents with reduced cardiac liability

  • Eur J Med Chem. 2025 Nov 5:297:117964. doi: 10.1016/j.ejmech.2025.117964.
Maria Maddalena Cavalluzzi 1,  Roberta Gualdani 2,  Alessandro Farinato 3,  Concetta Altamura 4,  Sabata Pierno 3,  Natalie Paola Rotondo 3,  Francesco Terlizzi 3,  Laura Beatrice Mattioli 5,  Maria Grazia Perrone 3,  Maria Cristina Lomuscio 6,  Giuseppe Felice Mangiatordi 7,  Nicola Antonio Colabufo 3,  Antonio Carrieri 3,  Roberta Budriesi 8,  Peter Gmeiner 9,  Harald Huebner 9,  Jean-François Desaphy 4,  Giovanni Lentini 3
Affiliations

Affiliations

  • 1 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125 Bari, Italy. Electronic address: mariamaddalena.cavalluzzi@uniba.it.
  • 2 Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.
  • 3 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125 Bari, Italy.
  • 4 Section of Pharmacology, Department of Precision and Regenerative Medicine, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy.
  • 5 Department of Pharmacy and Biotechnology, Food Chemistry and Nutraceutical Lab, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy; Health Sciences and Technologies-Interdepartmental Center for Industrial Research (CIRI-SDV), Alma Mater Studiorum University of Bologna, Bologna, Italy.
  • 6 Department of Precision and Regenerative Medicine and Jonian Area, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, Policlinico, 70124, Bari, Italy.
  • 7 CNR - Institute of Crystallography, 70126 Bari, Italy.
  • 8 Department of Pharmacy and Biotechnology, Food Chemistry and Nutraceutical Lab, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
  • 9 Department of Chemistry and Pharmacy, Friedrich-Alexander University, 91058 Erlangen, Germany.
PMID: 40652670 DOI: 10.1016/j.ejmech.2025.117964
Abstract

Lubeluzole is a neuroprotective agent displaying antimyotonic activity. Lubeluzole clinical development as an antiischemic drug was discontinued due to a lack of efficacy in human trials and possible cardiac toxicity. Since lubeluzole is a potent inhibitor of the hERG channel, involved in long QT syndromes and the potentially fatal cardiac arrhythmia Torsade de Pointes, a series of lubeluzole analogues were prepared to investigate the structural requirements to reduce the affinity for hERG channels to possibly obtain safe antimyotonic drugs. Compound 16o was identified as the less potent hERG blocker possibly endowed with lower cardiac liability in comparison with the parent compound. Antimyotonic activity of 16o was also investigated in vitro on hNav1.4 and higher use-dependence was observed in comparison to lubeluzole, thus suggesting greater selectivity toward highly excited tissues, such as the myotonic muscle. To further verify the cardiac safety of 16o, patch-clamp experiments on hNav1.5 were also carried out and a 3-fold reduction of potency in comparison with hNav1.4 in phasic block was observed. In vivo evaluation of the antimyotonic activity showed unintended effects on rat motor performance. Ex vivo studies suggested Calcium Channel blocking activity as a possible off-target source of the 16o unintended effects, also reinforced by possible interaction with β2 receptors, as indicated by in vitro binding assays and in silico studies. In conclusion, we think our results may support the rational design of lubeluzole analogues endowed with both antimyotonic activity and lower hERG liability.

Keywords

Lubeluzole; Myotonia; Sodium-channel blockers; Use-dependence; hERG liability.

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