Title:Recent Trends in the Discovery of Small Molecule Blockers of Sodium Channels
VOLUME: 23 ISSUE: 22
Author(s):Roberta Gualdani, Maria Maddalena Cavalluzzi and Giovanni Lentini
Affiliation:Università degli Studi di Bari Aldo Moro Dipartimento di Farmacia - Scienze del Farmaco Via E. Orabona 4 70125, Bari, Italy.
Keywords:Biophysics, Channelopathies, Chemotype, Drug discovery, Efficiency metrics, Electrophysiology,
Lead compound, Scaffold.
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.
