| Literature DB >> 29385334 |
Jelena Konstantinović1, Erkan Kiris2, Krishna P Kota3, Johanny Kugelman-Tonos3, Milica Videnović4, Lisa H Cazares3, Nataša Terzić Jovanović5, Tatjana Ž Verbić1, Boban Andjelković1, Allen J Duplantier3, Sina Bavari6, Bogdan A Šolaja1,7.
Abstract
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 are 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 min postintoxication. 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 postexposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, q.d. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series.Entities:
Mesh：
Substances：
Year: 2018 PMID： 29385334 PMCID： PMC5833296 DOI： 10.1021/acs.jmedchem.7b01710
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446