Advances in Targeting Voltage‐Gated Sodium Channels with Small Molecules

Abstract

Blockade of voltage-gated sodium channels (VGSCs) has been used successfully in the clinic to enable control of pathological firing patterns that occur in conditions as diverse as chronic pain, epilepsy, and arrhythmias. Herein we review the state of the art in marketed sodium channel inhibitors, including a brief compendium of their binding sites and of the cellular and molecular biology of sodium channels. Despite the preferential action of this drug class toward over-excited cells, which significantly limits potential undesired side effects on other cells, the need to develop a second generation of sodium channel inhibitors to overcome their critical clinical shortcomings is apparent. Current approaches in drug discovery to deliver novel and truly innovative sodium channel inhibitors is next presented by surveying the most recent medicinal chemistry breakthroughs in the field of small molecules and developments in automated patch-clamp platforms. Various strategies aimed at identifying small molecules that target either particular isoforms of sodium channels involved in specific diseases or anomalous sodium channel currents, irrespective of the isoform by which they have been generated, are critically discussed and revised.

Voltage gated sodium channels as drug discovery targets

“…In addition to measuring mRNA and protein expression levels from ex vivo studies, mice with knock-in, knock-out or conditional expression of sodium channel genes have also been used to better understand the role of the sodium channel subtypes. 2,4,10 From the various studies, Na V 1.1 and Na V 1.2 mutations have a genetic link to epilepsy and related CNS disorders whilst Na V 1.5 mutations have significant relation to cardiac arrhythmias. Periodic paralyses are caused by mutations in Na V 1.4, while the Na V 1.6 channel has been associated with cerebellar atrophy, behavioural deficits and ataxia.…”

“…2 In particular they have been applied to CNS conditions such as anti-convulsants e.g. carbamazepine (5), and epilepsy therapy e.g.…”

“…These subtypes are predominately expressed in sensory neurons with a link to nociception and therefore provide strong rationale as targets for the development of novel pain therapeutics. 2,10 Whilst subtypes Na V 1.1 and Na V 1.2 have been associated with the treatment of a variety of disorders they are also implicated in CNS mediated side effects, resulting in a narrow therapeutic index for many of the modulators. Furthermore, pro-arrhythmic effects resulting from block of Na V 1.5 channels presents a potential cardiac liability.…”

“…Selected examples described below. 2,3,[26][27][28] Patents from Vertex based on TTX-S channel modulators containing a weakly acidic N-heterocylic sulfonamide suggest Na V 1.1 and Na V 1.3 to be the preferred targets with compound 13 exhibiting IC 50 <2 mM at both Na V 1.1 and Na V 1.3 (Fig. 6).…”

“…lamotrigine, flecainide and lidocaine. [1][2][3] The Na V channel family has nine members (Na V 1.1 to Na V 1.9) with a high degree of sequence homology between the nine subtypes. A number of natural toxins such as tetrodotoxin (TTX) block the sodium channel extracellular pore, and the sensitivity of the sodium channel subtypes to blockade by TTX has been used to divide the family into two classes: (i) TTX-S (sensitive), TTX IC 50 <30 nM against Na V 1.1, 1.2, 1.3, 1.4, 1.6, 1.7 and (ii) TTX-R (resistant), TTX IC 50 >30 nM against Na V 1.5, 1.8 and Na v 1.9.…”