Sodium channel blockers: a patent review (2010 – 2014)

Abstract

Over the past 4 years we assisted to a continuous effort in the discovery of new sodium channel blockers by a large number of pharmaceutical companies. All the different chemical classes presented, and here analyzed, could represent an important breakout but, the lack of precise structural information, with the incompleteness of the biological data hampered the possibility to understand the real 'state of the art' of any of these inventions. Upon analysis of a number of patents in this review, it remains clear that the major hurdle faced by the discovery teams is the ability to develop subtype selective compounds. The development of subtype selective blockers could, in theory, lead to more effective and better tolerated compounds.

Retracted: Addition of a single methyl group to a small molecule sodium channel inhibitor introduces a new mode of gating modulation

“…McCormack and colleagues (2013) demonstrated that interaction with three amino acid residues on the extracellular facing S2 and S3 transmembrane segments of the Domain 4 voltage sensor was important for both activity and selectivity for both Na v 1.7 and Na v 1.3 selective members of an aryl sulfonamide class of Na v channel inhibitors. To better understand the structure-activity relationships underlying this subtype selective interaction, additional aryl sulfonamide and structurally related agents have been generated and characterized (Bagal et al, 2014;Zuliani et al, 2015). During these efforts, two compounds (PF-05661014 and PF-06526290), which differ only by a methyl moiety, have been evaluated.…”

Neurology—the next 10 years

“…59 In concert, therapeutic molecules that block specific subtypes of sodium channels while sparing others are under development. 60 Advanced techniques for atomic-level molecular modelling, 61 together with the solution of the crystal structure of prototypical bacterial sodium channels, have propelled molecular pharmacology to new levels.…”

Gene und Schmerz

“…Auf Einzelfallebene spielen Polymorphismen diagnostisch bisher keine bedeutende Rolle, jedoch könnte ihnen in Zukunft eine wichtige Funktion zukommen, wenn es darum geht, anhand von Fehlregulationen bestimmter Systeme eine "maßgeschneiderte" Therapie für Patienten zu planen. Selektiv auf Nav1.7-Kanäle wirkende Pharmaka sind seit Langem in der Entwicklung [42][43][44], jedoch ist diese nicht unproblematisch, da es schwierig zu sein scheint, Substanzen mit hoher Selektivität herzustellen [45].…”