Design, Synthesis, and Biological Evaluation of a New Series of Carvedilol Derivatives That Protect Sensory Hair Cells from Aminoglycoside-Induced Damage by Blocking the Mechanoelectrical Transducer Channel

• Published in: Journal of medicinal chemistry 2019-06, Vol.62 (11), p.5312-5329
• Main Authors: O’Reilly, Molly, Kirkwood, Nerissa K, Kenyon, Emma J, Huckvale, Rosemary, Cantillon, Daire M, Waddell, Simon J, Ward, Simon E, Richardson, Guy P, Kros, Corné J, Derudas, Marco
• Format: Article
• Language: English
• Subjects: Aminoglycosides - adverse effects; Animals; Carvedilol - chemical synthesis; Carvedilol - chemistry; Carvedilol - pharmacology; Chemistry Techniques, Synthetic; Cytoprotection - drug effects; Dose-Response Relationship, Drug; Drug Design; Electrophysiological Phenomena - drug effects; Hair Cells, Auditory - cytology; Hair Cells, Auditory - drug effects; Mechanotransduction, Cellular - drug effects; Mice; Zebrafish
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01325

Aminoglycosides (AGs) are broad-spectrum antibiotics used for the treatment of serious bacterial infections but have use-limiting side effects including irreversible hearing loss. Here, we assessed the otoprotective profile of carvedilol in mouse cochlear cultures and in vivo zebrafish assays and investigated its mechanism of protection which, we found, may be mediated by a block of the hair cell’s mechanoelectrical transducer (MET) channel, the major entry route for the AGs. To understand the full otoprotective potential of carvedilol, a series of 18 analogues were prepared and evaluated for their effect against AG-induced damage as well as their affinity for the MET channel. One derivative was found to confer greater protection than carvedilol itself in cochlear cultures and also to bind more tightly to the MET channel. At higher concentrations, both carvedilol and this derivative were toxic in cochlear cultures but not in zebrafish, suggesting a good therapeutic window under in vivo conditions.