title: NVP-QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia.
abstract: OBJECTIVE
  Inhaled amiloride, a blocker of the epithelial sodium channel (ENaC), enhances mucociliary clearance (MCC) in cystic fibrosis (CF) patients. However, the dose of amiloride is limited by the mechanism-based side effect of hyperkalaemia resulting from renal ENaC blockade. Inhaled ENaC blockers with a reduced potential to induce hyperkalaemia provide a therapeutic strategy to improve mucosal hydration and MCC in the lungs of CF patients. The present study describes the preclinical profile of a novel ENaC blocker, NVP-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia.
  
  
  METHODS
  The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) by short-circuit current. In vivo efficacy and safety were assessed in guinea pig (tracheal potential difference/hyperkalaemia), rat (hyperkalaemia) and sheep (MCC).
  
  
  RESULTS
  In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 attenuated ENaC activity in the guinea pig airways with greater potency and duration of action than that of amiloride without inducing hyperkalaemia in either guinea pig or rat. Dry powder inhalation of NVP-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action.
  
  
  CONCLUSIONS
  NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds.
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Coote
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: D
authors.initials: D
authors.lastname: Paisley
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Czarnecki
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: M
authors.initials: M
authors.lastname: Tweed
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: H
authors.initials: H
authors.lastname: Watson
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: A
authors.initials: A
authors.lastname: Young
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: R
authors.initials: R
authors.lastname: Sugar
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: M
authors.initials: M
authors.lastname: Vyas
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: Smith
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: U
authors.initials: U
authors.lastname: Baettig
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Groot-Kormelink
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: M
authors.initials: M
authors.lastname: Gosling
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: R
authors.initials: R
authors.lastname: Lock
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: B
authors.initials: B
authors.lastname: Ethell
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: G
authors.initials: G
authors.lastname: Williams
authors.affiliation: Genomics Institute of the Novartis Foundation, San Diego, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Schumacher
authors.affiliation: Genomics Institute of the Novartis Foundation, San Diego, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Harris
authors.affiliation: Department of Research, Mount Sinai Medical Center, Miami, FL, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Abraham
authors.affiliation: Department of Research, Mount Sinai Medical Center, Miami, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sabater
authors.affiliation: Retroscreen Virology Ltd, London, UK.
authors.forename: C T
authors.initials: CT
authors.lastname: Poll
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: T
authors.initials: T
authors.lastname: Faller
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.
authors.forename: S P
authors.initials: SP
authors.lastname: Collingwood
authors.affiliation: Novartis Institutes for BioMedical Research, Horsham, UK.|School of Life Sciences, University of Sussex, Brighton, UK.
authors.forename: H
authors.initials: H
authors.lastname: Danahay
mesh_terms: D000280:Administration, Inhalation; D000584:Amiloride / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D004847:Epithelial Cells / Q000187:drug effects*; D062686:Epithelial Sodium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology*; D006146:Guanidines; D006168:Guinea Pigs; D006947:Hyperkalemia / Q000139:chemically induced*; D066298:In Vitro Techniques; D009079:Mucociliary Clearance / Q000187:drug effects*; D010647:Phenyl Ethers / Q000009:adverse effects / Q000494:pharmacology*; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology*; D011719:Pyrazines; D051381:Rats; D020545:Respiratory Mucosa / Q000166:cytology; D012756:Sheep
chemical_list: D062686:Epithelial Sodium Channel Blockers; D006146:Guanidines; C513153:N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N'-(4-(4-(2,3-dihydroxypropoxy)phenyl)butyl)guanidine; C000604937:NVP-QBE170; D010647:Phenyl Ethers; D010880:Piperidines; D011719:Pyrazines; D000584:Amiloride