New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Post-intoxication Model

The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene and adamantane 4 aminoquinoline derivatives is described. In addition, the compounds were evaluated for th...

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Published in:Journal of medicinal chemistry 2018-02, Vol.61 (4), p.1595-1608
Main Authors: Konstantinović, Jelena, Kiris, Erkan, Kota, Krishna P., Tonos, Johanny Kugelman, Videnović, Milica, Cazares, Lisa H., Jovanović, Nataša Terzić, Verbić, Tatjana Ž., Andjelković, Boban, Duplantier, Allen J., Bavari, Sina, Šolaja, Bogdan A.
Format: Article
Language:English
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Summary:The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene and adamantane 4 aminoquinoline derivatives is described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP 25) even when administered 30 minutes post intoxication. This appears to be the first example of LC inhibitors antagonizing BoNT intoxication in mouse embryonic stem cell derived motor neurons (mES MNs) in a post-exposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, qd. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01710