Pharmacological Properties of N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine Methanesulfonate (552-02), a Novel Epithelial Sodium Channel Blocker with Potential Clinical Efficacy for Cystic Fibrosis Lung Disease

@article{Hirsh2008PharmacologicalPO,
  title={Pharmacological Properties of N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine Methanesulfonate (552-02), a Novel Epithelial Sodium Channel Blocker with Potential Clinical Efficacy for Cystic Fibrosis Lung Disease},
  author={Andrew James. Hirsh and Jim Zhang and Andra Zamurs and Jacquelyn Fleegle and William R Thelin and Ray A. Caldwell and Juan R. Sabater and William M. Abraham and Mark Donowitz and Boyoung Cha and Kevin B. Johnson and Judith A. St. George and M. Ross Johnson and Richard C. Boucher},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2008},
  volume={325},
  pages={77 - 88}
}
Amiloride improves mucociliary clearance (MC) by blocking airway epithelial sodium channels (ENaC) and expanding airway surface liquid (ASL). However, the low potency and rapid absorption of amiloride by airway epithelia translated into a short duration of efficacy as an aerosolized therapy for cystic fibrosis (CF) patients. To improve ENaC blocker CF pharmacotherapy, a more potent and durable ENaC blocker tailored for aerosol delivery was synthesized. Parion compound N-(3,5-diamino-6… Expand
Composés 3,5-diamino -6-chloro-n-(n- (4-phénylbutyl)carbamimidoyl) pyrazine-2-carboxamide
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TLDR
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TLDR
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TLDR
This study establishes the proof of concept that a reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease. Expand
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TLDR
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References

SHOWING 1-10 OF 51 REFERENCES
Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: drugs for cystic fibrosis and chronic bronchitis.
TLDR
Lead compound 32 was 102-fold more potent and 5-fold less reversible than amiloride and displayed the lowest IC(50) value ever reported for an ENaC blocker. Expand
Evaluation of Second Generation Amiloride Analogs as Therapy for Cystic Fibrosis Lung Disease
TLDR
The hypothesis that ENaC blocker aerosol therapy increases MC is supported, however, rapid absorption of benzamil from the mucosal surface offset its greater potency, making it equieffective with amiloride in vivo. Expand
Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: Results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis
TLDR
D doses up to 60 mg of denufosol inhalation solution were well‐tolerated in most subjects, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y2 agonists. Expand
On the Interaction between Amiloride and Its Putative α-Subunit Epithelial Na+ Channel Binding Site*
TLDR
It is concluded that amiloride binds at or near this site and that αSer-583 may have a role in ion permeation through ENaC. Expand
Aerosolized amiloride: dose effect on nasal bioelectric properties, pharmacokinetics, and effect on sputum expectoration in patients with cystic fibrosis.
TLDR
The bioelectric effects of amiloride and serum levels after inhalation are dose dependent, and amILoride is effective at inducing sputum expectoration in CF. Expand
Deposition, clearance, and effects of aerosolized amiloride in sheep airways.
TLDR
It is concluded that sufficient concentrations of amiloride can be delivered to sheep airways by aerosol to inhibit PD and Na+ absorption for short periods and is consistent with the rapid clearance from the airway surface and the short-lived effects of aerosolized amILoride in vivo. Expand
Amiloride and its analogs as tools in the study of ion transport
TLDR
The use of amiloride and its analogs in the study of ion transport requires a knowledge of the pharmacology of inhibition of transport proteins, as well as effects on enzymes, receptors, and other cellular processes, such as DNA, RNA, and protein synthesis, and cellular metabolism. Expand
Identification of Amino Acid Residues in the α, β, and γ Subunits of the Epithelial Sodium Channel (ENaC) Involved in Amiloride Block and Ion Permeation
TLDR
It is proposed that amiloride interacts with Na+ions at an external Na+binding site preventing ion permeation through the channel pore, and may form a pore loop structure at the extracellular face of the channel, where amILoride binds within the channel lumen. Expand
Acute and long-term amiloride inhalation in cystic fibrosis lung disease. A rational approach to cystic fibrosis therapy.
TLDR
Amiloride inhalation administered as a single dose or as long-term therapy is able to increase MC and CC in CF airways and that the effect of 10(-3) M amilorides inhalation on MC lasts at least 40 min. Expand
Inhalation of Moli1901 in patients with cystic fibrosis.
TLDR
The inhalation of Moli1901 up to a total cumulative dose of 12.5 mg appears to be safe in adult patients with CF and had a sustained beneficial effect on pulmonary function, which supports further studies of its efficacy in CF patients. Expand
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