Title: Substituted 4-phenyl-2-aminoimidazoles and 4-phenyl-4,5-dihydro-2-aminoimidazoles as voltage-gated sodium channel modulators
Authors: Zidar, Nace ×
Jakopin, Ziga
Madge, David J
Chan, Fiona
Tytgat, Jan
Peigneur, Steve
Dolenc, Marija Sollner
Tomašić, Tihomir
Ilaš, Janez
Mašič, Lucija Peterlin
Kikelj, Danijel #
Issue Date: Mar-2014
Series Title: European Journal of Medicinal Chemistry vol:74 pages:23-30
Article number: 10.1016/j.ejmech.2013.12.034
Abstract: Voltage-gated sodium channels play an integral part in neurotransmission and their dysfunction is frequently a cause of various neurological disorders. On the basis of the structure of marine alkaloid clathrodin, twenty eight new analogs were designed, synthesized and tested for their ability to block human NaV1.3, NaV1.4 and NaV1.7 channels, as well as for their selectivity against human cardiac isoform NaV1.5, using automated patch clamp electrophysiological assay. Several compounds exhibited promising activities on different NaV channel isoforms in the medium micromolar range and some of the compounds showed also moderate isoform selectivities. The most promising results were obtained for the NaV1.3 channel, for which four compounds were found to possess IC50 values lower than 15 μM. All of the active compounds bind to the open-inactivated states of the channels and therefore act as state-dependent modulators. The obtained results validate the approach of using natural products driven chemistry for drug discovery starting points and represent a good foundation for future design of selective NaV modulators.
ISSN: 0223-5234
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Toxicology and Pharmacology
× corresponding author
# (joint) last author

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