Sodium Channel inhibitor 1

Description: IC50 Value: 0.16 uM ( Na v1.7, V hold-90mV); 0.41 uM (Na v1.7, V hold-90mV) [1] Sodium Channel inhibitor1, one of 3-Oxoisoindoline-1-carboxamides, is a novel and selective voltage-gated sodium channel for pain treatment. Sodium Channel inhibitor1 demonstrated concentration-dependent e?cacy in preclinical behavioral pain models.

Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine.[Pubmed:27080178]

Bioorg Med Chem Lett. 2016 Jul 1;26(13):3202-3206.

We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and beta-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late INa current inhibition and lack of Peak INa inhibition led to the discovery of 4h (GS-458967) with improved anti-arrhythmic activity relative to ranolazine. Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central and peripheral nervous system isoforms that is consistent with its low therapeutic index (approximately 5-fold in rat, 3-fold in dog). Compound 4h represents our initial foray into a 2nd generation Late INa inhibitor program and is an important proof-of-concept compound. We will provide additional reports on addressing the CNS challenge in a follow-up communication.

Compound-specific effects of mutations at Val787 in DII-S6 of Nav 1.4 sodium channels on the action of sodium channel inhibitor insecticides.[Pubmed:22983119]

Neurotoxicology. 2012 Oct;33(5):1381-9.

Sodium channel inhibitor (SCI) insecticides are hypothesized to inhibit voltage-gated sodium channels by binding selectively to the slow-inactivated state. Replacement of valine at position 787 in the S6 segment of homology domain II of the rat Na(v)1.4 sodium channel by lysine (V787K) enchances slow inactivation of this channel whereas replacement by alanine or cysteine (V787A and V787C) inhibits slow inactivation. To test the hypothesis that SCI insecticides bind selectively to the slow-inactivated state, we constructed mutated Na(v)1.4/V787A, Na(v)1.4/V787C, and Na(v)1.4/V787K cDNAs, expressed wildtype and mutated channels with the auxiliary beta1 subunit in Xenopus oocytes, and used the two-electrode voltage clamp technique to examine the effects of these mutations on channel inhibition by four SCI insecticides (indoxacarb, its bioactivated metabolite DCJW, metaflumizone, and RH3421). Mutations at Val787 affected SCI insecticide sensitivity in a manner that was independent of mutation-induced changes in slow inactivation gating. Sensitivity to inhibition by 10 muM indoxacarb was significantly increased in all three mutated channels, whereas sensitivity to inhibition by 10 muM metaflumizone was significantly reduced in Na(v)1.4/V787A channels and completely abolished in Na(v)1.4/V787K channels. The effects of Val787 mutations on metaflumizone were correlated with the hydrophobicity of the substituted amino acid rather than the extent of slow inactivation. None of the mutations at Val787 significantly affected the sensitivity to inhibition by DCJW or RH3421. These results demonstrate that the impact of mutations at Val787 on sodium channel inhibition by SCI insecticides depend on the specific insecticide examined and is independent of mutation-induced changes in slow inactivation gating. We propose that Val787 may be a unique determinant of metaflumizone binding.

Sodium Channel inhibitor1, one of 3-Oxoisoindoline-1-carboxamides, is a novel and selective voltage-gated sodium channel for pain treatment.

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