Design, Synthesis, and Structure−Activity Relationships of Novel 2-Substituted Pyrazinoylguanidine Epithelial Sodium Channel Blockers:  Drugs for Cystic Fibrosis and Chronic Bronchitis

Hirsh, Andrew J.; Molino, Bruce F.; Zhang, Jianzhong; Astakhova, N. А.; Geiss, William; Sargent, Bruce J.; Swenson, Brian D.; Usyatinsky, Alexander; Wyle, Michael J.; Boucher, Richard C.; Smith, Rick T.; Zamurs, and Andra; Johnson, Melissa

doi:10.1021/jm051134w

Cited by 74 publications

(51 citation statements)

References 40 publications

(191 reference statements)

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“…9,13 EnNaC may present a specific target for therapeutic intervention if its inhibition can be functionally separated from EpNaC, and thus avoiding or at least minimizing impairment of renal and intestinal K + secretion. Recent developments of novel 2-acyl-amiloride derivatives 18,19 may provide a potential avenue for further development. An interesting analogue would have reasonable bioavailabilty (oral, sublingual, or transdermal), with hepatobiliary rather than renal clearance, and effectiveness as a noncompetitive inhibitor against EnNaC at subnanomolar concentrations.…”

Section: Warnock Vascular Tone and Ennac 953mentioning

confidence: 99%

The Amiloride-Sensitive Endothelial Sodium Channel and Vascular Tone

Warnock

2013

Hypertension

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Further work to precisely define the subunit structures and assembly, the possibility of alternative transcription start sites or splicing, and even other subunits 12 need to be fully explored. As an example, in the original clinical phenotype of the autosomal dominant gain-of-function condition by Liddle et al, 13 there was a striking effect of increased dietary sodium intake (and presumably increased urinary sodium concentration) to reduce the effectiveness of sodium channel blockade observed with triamterene. In contrast, EnNaC activity as described in the current report by Jeggle and colleagues was fully inhibited by amiloride in the presence of normal extracellular sodium concentrations of 140 mmol/L. A recent report by Kleyman and colleagues describes a novel point mutation in the γ ENaC subunit (γL511Q) that increases amiloride-sensitive currents and largely eliminates the Na + self-inhibition response, which reflects downregulation of ENaC open probability by higher extracellular Na + concentrations. This sort of downregulation would be appropriate for the amiloride-sensitive EpNaC in the distal nephron but would not be relevant for EnNaC in the systemic circulation that is continuously bathed in relative higher extracellular Na + concentrations. Hence, sequence variations in the γ ENaC subunit at the single nulceotide level could have important conseqences for understanding the regulation of EnNaC activity.It is well recognized that renin-angiotension-aldosterone system blockade is an important avenue for treating chronic kidney disease and reducing mortality in cardiovascular disease. Major efforts have demonstrated the clinical benefit of using mineralocorticoid receptor antagonism in cardiovascular disease, with novel new approaches coming to the fore.14 Unfortunately, the cardioprotective effects associated with mineralocorticoid receptor blockade nearly 15 years ago 15 are not readily available to patients with moderate-tosevere chronic kidney disease who can develop dose-limiting hyperkalemia in the setting of aggressive renin-angiotensionaldosterone system blockade, such as described in the recent ALTITUDE Trial. 16 Previous consideration has been given to trying to separate the effects of Na-channel blockers like amiloride or triamterene from the parallel decreases in K + secretion that invariably accompany EpNaC blockade. Furthermore, the currently available EpNaC blockers do not have a substantial effect on reduction of systemic blood pressure, at least in the currently used dosing regimens. 17 An exception to this overall analysis is provided by the salulatory responses to amiloride in adolescents with Liddle syndrome, who presumably have not developed the long-term vascular changes associated with chronic hypertension, although this effect may represent a primary renal effect rather than an effect on the vascular endothelium in Liddle syndrome and is clearly predicated on control of dietary salt intake. 9,13EnNaC may present a specific target for therapeutic intervention if its inhibition ca...

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Section: Warnock Vascular Tone and Ennac 953mentioning

confidence: 99%

The Amiloride-Sensitive Endothelial Sodium Channel and Vascular Tone

Warnock

2013

Hypertension

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“…The concentration of amiloride yielding 50% ENaC inhibition (IC 50 ) is ϳ100 nM, whereas the more potent and specific derivatives phenamil and benzamil exhibit IC 50 values ϳ10 nM. Thus, high affinity ENaC blockers have been identified (9).…”

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confidence: 99%

Small Molecule Activator of the Human Epithelial Sodium Channel

Lü¹,

Echeverri²,

Kalabat³

et al. 2008

Journal of Biological Chemistry

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The epithelial sodium channel (ENaC), a heterotrimeric complex composed of ␣, ␤, and ␥ subunits, belongs to the ENaC/ degenerin family of ion channels and forms the principal route for apical Na ؉ entry in many reabsorbing epithelia. Although high affinity ENaC blockers, including amiloride and derivatives, have been described, potent and specific small molecule ENaC activators have not been reported. Here we describe compound S3969 that fully and reversibly activates human ENaC (hENaC) in an amiloride-sensitive and dose-dependent manner in heterologous cells. Mechanistically, S3969 increases hENaC open probability through interactions requiring the extracellular domain of the ␤ subunit. hENaC activation by S3969 did not require cleavage by the furin protease, indicating that nonproteolyzed channels can be opened. Function of ␣␤G37S␥ hENaC, a channel defective in gating that leads to the salt-wasting disease pseudohypoaldosteronism type I, was rescued by S3969. Small molecule activation of hENaC may find application in alleviating human disease, including pseudohypoaldosteronism type I, hypotension, and neonatal respiratory distress syndrome, when improved Na ؉ flux across epithelial membranes is clinically desirable.

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“…Pyrazine is a six membered hetero-aromatic ring usually found in the structure of numerous natural products and synthetic compounds, some of which are used in the food industry for their flavor properties [222][223][224]. Moreover, they are versatile synthetic intermediates [225], and many functionalized pyrazines possess pharmacological activities, such as antiviral [226,227] (242, 243), ATR kinase inhibitor [228] (244), antitumor [229], vascular endothelial growth factor inhibitory activity [230], or as epithelial sodium channel blockers [231] (Figure 15). Pyrazine is a six membered hetero-aromatic ring usually found in the structure of numerous natural products and synthetic compounds, some of which are used in the food industry for their flavor properties [222][223][224].…”

Section: Scheme 48 Mw-assisted Ugi 4-component Reaction Leading To Pmentioning

confidence: 99%

“…Moreover, they are versatile synthetic intermediates [225], and many functionalized pyrazines possess pharmacological activities, such as antiviral [226,227] (242, 243), ATR kinase inhibitor [228] (244), antitumor [229], vascular endothelial growth factor inhibitory activity [230], or as epithelial sodium channel blockers [231] (Figure 15). Original synthetic heterocycles, such as substituted dicyanopyrazines 247, 248, have been synthesized using a domestic MW oven [232].…”

Section: Scheme 48 Mw-assisted Ugi 4-component Reaction Leading To Pmentioning

confidence: 99%

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

et al. 2016

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This review describes the formation of six-membered heterocyclic compounds and their fused analogues under microwave activation using modern organic transformations including cyclocondensation, cycloaddition, multicomponents and other modular reactions. The review is divided according to the main heterocycle types in order of increasing complexity, starting with heterocyclic systems containing one, two and three heteroatoms and their fused analogues. Recent microwave applications are reviewed, with special focus on the chemistry of bioactive compounds. Selected examples from the 2006 to 2015 literature are discussed.

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Design, Synthesis, and Structure−Activity Relationships of Novel 2-Substituted Pyrazinoylguanidine Epithelial Sodium Channel Blockers: Drugs for Cystic Fibrosis and Chronic Bronchitis

Cited by 74 publications

References 40 publications

The Amiloride-Sensitive Endothelial Sodium Channel and Vascular Tone

The Amiloride-Sensitive Endothelial Sodium Channel and Vascular Tone

Small Molecule Activator of the Human Epithelial Sodium Channel

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

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