title: Inhibition of NaV1.6 sodium channel currents by a novel series of 1,4-disubstituted-triazole derivatives obtained via copper-catalyzed click chemistry.
abstract: We have synthesized and evaluated a series of 1,4-disubstituted-triazole derivatives for inhibition of the rat Na(V)1.6 sodium channel isoform, an isoform thought to play an important role in controlling neuronal firing. Starting from a series of 2,4(1H)-diarylimidazoles previously published, we decided to extend the SAR study by replacing the imidazole with a different heterocyclic scaffold and by varying the aryl substituents on the central aromatic ring. The 1,4-disubstituted 1,2,3-triazoles were prepared employing the copper-catalyzed azide-alkyne cycloaddition (CuAAC). Many of the new molecules were able to block the rNa(v)1.6 currents at 10 μM by over 20%, displaying IC(50) values ranging in the low micromolar, thus indicating that triazole can efficiently replace the central heterocyclic core. Moreover, the introduction of a long chain at C4 of the central triazole seems beneficial for increased rNa(v)1.6 current block, whereas the length of N1 substituent seems less crucial for inhibition, as long as a phenyl ring is not direcly connected to the triazole. These results provide additional information on the structural features necessary for block of the voltage-gated sodium channels. These new data will be exploited in the preparation of new compounds and could result in potentially useful AEDs.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy. mirko.rivara@unipr.it
authors.forename: Mirko
authors.initials: M
authors.lastname: Rivara
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Patel
authors.forename: Laura
authors.initials: L
authors.lastname: Amori
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuliani
mesh_terms: D000818:Animals; D002384:Catalysis; D057930:Click Chemistry; D003300:Copper / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000378:metabolism*; D051381:Rats; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; C507811:Scn8a protein, rat; D014230:Triazoles; D061567:Voltage-Gated Sodium Channel Blockers; D003300:Copper