Substituted 4-phenyl-2-aminoimidazoles and 4-phenyl-4,5-dihydro-2-aminoimidazoles as voltage-gated sodium channel modulators.
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.
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Nace
N
Zidar
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Žiga
Ž
Jakopin
Xention Limited, Iconix Park, London Road, Pampisford, Cambridge CB22 3EG, UK.
David J
DJ
Madge
Xention Limited, Iconix Park, London Road, Pampisford, Cambridge CB22 3EG, UK.
Fiona
F
Chan
University of Leuven (KU Leuven), Toxicology & Pharmacology, O&N2, PO Box 922, Herestraat 49, 3000 Leuven, Belgium.
Jan
J
Tytgat
University of Leuven (KU Leuven), Toxicology & Pharmacology, O&N2, PO Box 922, Herestraat 49, 3000 Leuven, Belgium.
Steve
S
Peigneur
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Marija Sollner
MS
Dolenc
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Tihomir
T
Tomašić
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Janez
J
Ilaš
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Lucija Peterlin
LP
Mašič
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia. Electronic address: danijel.kikelj@ffa.uni-lj.si.
Danijel
D
Kikelj
D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D015222:Sodium Channels / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared
D007093:Imidazoles; D015222:Sodium Channels
4-Phenyl-2-aminoimidazole; Clathrodin; Marine alkaloid; Na(V) channel modulator; Pyrrole-2-aminoimidazole; Voltage-gated sodium channel