Article Details
Recent Trends in the Discovery of Small Molecule Blockers of
Sodium Channels
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.
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.
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