Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Erdemli, Gül; Kim, Albert M.; Ju, Haisong; Springer, Clayton; Penland, Robert C.; Hoffmann, Peter

doi:10.3389/fphar.2012.00006

Cited by 45 publications

(25 citation statements)

References 55 publications

(77 reference statements)

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“…By an automated patch clamp study in WT Nav1.5, at least 50% of the hits have been validated. Extended from earlier observations from known drugs, this finding has demonstrated Nav1.5 is a promiscuous target using extensive experimental evidence from diverse compounds and provides a rationale to include Nav1.5 in the cardiac safety evaluation since Nav1.5 inhibition can lead to QRS complex prolongation (Erdemli et al, 2012). Indeed, a very Fig.…”

Section: Discussionmentioning

confidence: 59%

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Zhang

Zou

et al. 2014

Mol Pharmacol

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Voltage-gated sodium (Nav) channels are essential for membrane excitability and represent therapeutic targets for treating human diseases. Recent reports suggest that these channels, e.g., Nav1.3 and Nav1.5, are inhibited by multiple structurally distinctive small molecule drugs. These studies give reason to wonder whether these drugs collectively target a single site or multiple sites in manifesting such pharmacological promiscuity. We thus investigate the pharmacological profile of Nav1.5 through systemic analysis of its sensitivity to diverse compound collections. Here, we report a dual-color fluorescent method that exploits a customized Nav1.5 [calcium permeable Nav channel, subtype 5 (SoCal5)] with engineered-enhanced calcium permeability. SoCal5 retains wildtype (WT) Nav1.5 pharmacological profiles. WT SoCal5 and SoCal5 with the local anesthetics binding site mutated (F1760A) could be expressed in separate cells, each with a differentcolored genetically encoded calcium sensor, which allows a simultaneous report of compound activity and site dependence. The pharmacological profile of SoCal5 reveals a hit rate (.50% inhibition) of around 13% at 10 mM, comparable to that of hERG. The channel activity is susceptible to blockage by known drugs and structurally diverse compounds. The broad inhibition profile is highly dependent on the F1760 residue in the inner cavity, which is a residue conserved among all nine subtypes of Nav channels. Both promiscuity and dependence on F1760 seen in Nav1.5 were replicated in Nav1.4. Our evidence of a broad inhibition profile of Nav channels suggests a need to consider off-target effects on Nav channels. The site-dependent promiscuity forms a foundation to better understand Nav channels and compound interactions.

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Section: Discussionmentioning

confidence: 59%

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Zhang

Zou

et al. 2014

Mol Pharmacol

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“…These isoforms are differentially expressed throughout the body, but inhibition of Na V 1.5, which is expressed in cardiac tissue, is of particular concern as it has been shown to prolong the cardiac QRS wave in humans. 5,6 Previous efforts, including our own, have met with limited success. 4 Here we report the characterization, structure−activity relationship (SAR) and optimization of a series of sulfonamide-derived Na V 1.7 inhibitors.…”

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confidence: 99%

“…Adding additional polarity in the form of quinazoline 16 led to further improvements in Na V 1.7 potency, although at the cost of a slight increase in unbound clearance. Compounds 17 and 18, which demonstrated lower cLogDs, also demonstrated higher unbound clearance, while shifting polarity to the upper ring of the [6,6] system led to loss of Na V 1.7 potency (e.g., naphthyridine 19). Ultimately, quinazoline 16 afforded the best combination of Na V 1.7 potency, permeability, and unbound clearance.…”

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confidence: 99%

Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

Marx

Dineen

Able

et al. 2016

ACS Med. Chem. Lett.

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Human genetic evidence has identified the voltage-gated sodium channel Na V 1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of Na V 1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining Na V 1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing. KEYWORDS: Sodium channel, Na V 1.7, Na V 1.5, pain, histamine scratching model H uman genetics has implicated the voltage-gated sodium channel Na V 1.7, which is expressed in nociceptive sensory neurons in dorsal root ganglia (DRG), 1 as a compelling target for pain.2−4 The primary challenge associated with the development of Na V 1.7 inhibitors has historically been achieving selectivity over the other eight Na V isoforms. These isoforms are differentially expressed throughout the body, but inhibition of Na V 1.5, which is expressed in cardiac tissue, is of particular concern as it has been shown to prolong the cardiac QRS wave in humans. 5,6 Previous efforts, including our own, have met with limited success. 4 Here we report the characterization, structure−activity relationship (SAR) and optimization of a series of sulfonamide-derived Na V 1.7 inhibitors. These efforts delivered an isoform-selective compound that was effective in a histamine-induced scratching model that is representative of Na V 1.7 target engagement. Recently Pfizer and Icagen described a series of heteroarylsulfonamide Na V 1.7 inhibitors with high levels of selectivity over Na V 1.5. 7−9 These results were reproduced by our group and are exemplified by compound 1 (Figure 1A). The lack of Na V 1.5 activity was noteworthy, and we envisioned this as a good starting point for our own lead optimization efforts, which would initially be aimed at addressing some of the liabilities and shortcomings associated with this class of compounds. Namely, this series suffered from low passive permeability and high clearance in rodents. We believed constraining the linker within a bicyclic core such as indole 2 or naphthalene 3 would afford a similar conformation and potentially help address the pharmacokinetic liabilities of this class of compounds. An overlay of global minima conformations of compounds 1, 2, and 3 supported this hypothesis ( Figure 1B), 10 and we were pleased to find that 2 and 3 were potent Na V 1.7 inhibitors and showed greater than 200-fold selectivity over Na V 1.5 ( Figure 1C). 11 In general, analogues in the naphthalene series demonstrated superior Na V 1.7 inhibition compared to the corresponding indole analogues, thus the naphthalene scaffold was chosen for further optimization. Additional profiling showed 3 also suffered from high clearance; however, we believed that 3 represented a promising starting poin...

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“…In particular, inhibition of Na V 1.5, which is expressed in atrial and ventricular myocytes, has been shown to prolong the cardiac QRS wave in humans, causing a decrease in conduction velocity which may ultimately lead to adverse cardiovascular events. 8 Recently, we have reported the lead optimization of heteroaryl sulfonamides and biaryl acyl sulfonamides as potent Na V 1.7 inhibitors possessing a high degree of selectivity over other Na V isoforms. 9 Despite excellent potency and Na V 1.7 selectivity, the development of these sulfonamides has been hampered by several factors.…”

Section: Introductionmentioning

confidence: 99%

Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent Na_V1.7 inhibitors

Sparling

Able

et al. 2017

Med. Chem. Commun.

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Na1.7 is a particularly compelling target for the treatment of pain. Herein, we report the discovery and evaluation of a series of piperazine amides that exhibit state-dependent inhibition of Na1.7. After demonstrating significant pharmacodynamic activity with early lead compound in a Na1.7-dependent behavioural mouse model, we systematically established SAR trends throughout each sector of the scaffold. The information gleaned from this modular analysis was then applied additively to quickly access analogues that encompass an optimal balance of properties, including Na1.7 potency, selectivity over Na1.5, aqueous solubility, and microsomal stability.

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Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Cited by 45 publications

References 55 publications

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent Na_V1.7 inhibitors

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Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

Cited by 45 publications

References 55 publications

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Reporting Sodium Channel Activity Using Calcium Flux: Pharmacological Promiscuity of Cardiac Nav1.5

Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors

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Product

Resources

About

Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent Na_V1.7 inhibitors