title: 2,4(5)-diarylimidazoles as inhibitors of hNaV1.2 sodium channels: pharmacological evaluation and structure-property relationships.
abstract: Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal Na(V)1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D(7.4)) and basicity (pK(a)) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC(50) values that were considerably lower than our lead compound. In particular, the m-CF(3) disubstituted 22 was the most active compound, inhibiting hNa(V)1.2 currents within the nanomolar concentration range (IC(50)=200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC(50)'s values that were greater than 100 microM.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, Viale G.P. Usberti, 27/A, I-43100 Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fantini
authors.forename: Mirko
authors.initials: M
authors.lastname: Rivara
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuliani
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Kalmar
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.forename: Aparna R
authors.initials: AR
authors.lastname: Baheti
authors.forename: Natasha
authors.initials: N
authors.lastname: Singh
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Merrick
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Katari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cocconcelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghiron
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Patel
mesh_terms: D002460:Cell Line; D004594:Electrophysiology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D026941:Sodium Channel Blockers; D015222:Sodium Channels