Sodium Channel Blockers for the Treatment of Pain
2017; Elsevier BV; Linguagem: Inglês
10.1016/b978-0-12-409547-2.12439-4
AutoresDavid R. Witty, David T. MacPherson, Gerard M.P. Giblin,
Tópico(s)Neuroscience and Neuropharmacology Research
ResumoBlockade of sodium channels for the treatment of pain has been validated as a successful mechanism by a number of commercial drugs. Their therapeutic use is currently limited by lack of channel or mode specificity, low potency, and by polypharmacological toxicity. Following genetic profiling of individuals with a variety of pain conditions, a clearer understanding of the link between particular channelopathies and pain has been established. The first high-definition structures of sodium channels have been utilized by medicinal chemists, and a new generation of potent and selective channel blockers is now being developed. These typically target specific sodium channels with the greatest validation as pain targets, and are designed to engage modes of inhibition, or compartment localization, aimed at delivering an improved safety profile. This chapter analyzes chemical structures disclosed in recent papers and patent applications, and compares the medicinal chemistry approaches of different organizations and the pharmacophores and chemotypes developed for specific channels' binding sites or inhibition mechanisms. An analysis of peptidic and antibody approaches to sodium channel therapeutics is discussed, and the current progress of clinical candidates is summarized.
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