title: Recent Trends in the Discovery of Small Molecule Blockers of Sodium Channels.
abstract: Voltage-gated sodium channels (VGSC) are responsible for the selective influx of sodium ions in excitable cells. A number of physiological phenomena such as muscle contraction, pain sensation, processing of neuronal information in the brain as well as neuronal regulation of peripheral tissues rely on the activity of these channels. On the other hand, abnormal activity of VGSC are implicated in several pathological processes (e.g., cardiac arrhythmias, epilepsy, and chronic pain) which in some cases (e.g., channelopathies such as myotonias) are linked to specific gene mutations. As a result, VGSC have never stopped attracting the attention of medicinal chemists and the quest for novel drugs to treat these ion channels-associated diseases continues. In this review, VGSC blocking agents reported in the last lustrum are scrutinised with the aim to give a medicinal chemistry perspective on the most interesting compounds classified on the basis of (i) potential therapeutic application, (ii) targeted VGSC isoforms, and (iii) chemical scaffolds. Finally, the clinical potential of selected drug candidates from each chemotype is evaluated by comparing their ligand efficiency metrics. Possible routes for improvement of these preclinical candidates are also discussed.
authors.forename: Roberta
authors.initials: R
authors.lastname: Gualdani
authors.affiliation: Università degli Studi di Bari Aldo Moro Dipartimento di Farmacia - Scienze del Farmaco Via E. Orabona 4 70125, Bari, Italy.
authors.forename: Maria Maddalena
authors.initials: MM
authors.lastname: Cavalluzzi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lentini
mesh_terms: D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D055808:Drug Discovery / Q000639:trends; D004827:Epilepsy / Q000188:drug therapy; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D054852:Small Molecule Libraries; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels