Design, synthesis and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechano-electrical transducer channel

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Design, synthesis and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechano-electrical transducer channel. / O'reilly, Molly; Kirkwood, Nerissa K; Kenyon, Emma J; Huckvale, Rosemary; Cantillon, Daire M; Waddell, Simon J; Ward, Simon E; Richardson, Guy P; Kros, Corne J.; Derudas, Marco.

In: Journal of Medicinal Chemistry, Vol. 62, No. 11, 13.06.2019, p. 5312-5329.

Research output: Contribution to journalArticlepeer-review

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O'reilly, Molly ; Kirkwood, Nerissa K ; Kenyon, Emma J ; Huckvale, Rosemary ; Cantillon, Daire M ; Waddell, Simon J ; Ward, Simon E ; Richardson, Guy P ; Kros, Corne J. ; Derudas, Marco. / Design, synthesis and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechano-electrical transducer channel. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 11. pp. 5312-5329.

Bibtex

@article{0db55d2a43c841b4bc31684f39404b63,
title = "Design, synthesis and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechano-electrical transducer channel",
abstract = "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.",
author = "Molly O'reilly and Kirkwood, {Nerissa K} and Kenyon, {Emma J} and Rosemary Huckvale and Cantillon, {Daire M} and Waddell, {Simon J} and Ward, {Simon E} and Richardson, {Guy P} and Kros, {Corne J.} and Marco Derudas",
year = "2019",
month = jun,
day = "13",
doi = "10.1021/acs.jmedchem.8b01325",
language = "English",
volume = "62",
pages = "5312--5329",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "11",

}

RIS

TY - JOUR

T1 - Design, synthesis and biological evaluation of a new series of carvedilol derivatives that protect sensory hair cells from aminoglycoside-induced damage by blocking the mechano-electrical transducer channel

AU - O'reilly, Molly

AU - Kirkwood, Nerissa K

AU - Kenyon, Emma J

AU - Huckvale, Rosemary

AU - Cantillon, Daire M

AU - Waddell, Simon J

AU - Ward, Simon E

AU - Richardson, Guy P

AU - Kros, Corne J.

AU - Derudas, Marco

PY - 2019/6/13

Y1 - 2019/6/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85066394727&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.8b01325

DO - 10.1021/acs.jmedchem.8b01325

M3 - Article

VL - 62

SP - 5312

EP - 5329

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 11

ER -