Coote, K J, Paisley, D, Czarnecki, S, Tweed, M, Watson, H, Young, A, Sugar, R, Vyas, M, Smith, N J, Baettig, U, Groot-Kormelink, P J, Gosling, Martin, Lock, R, Ethell, B, Williams, G, Schumacher, A, Harris, J, Abraham, W M, Sabater, J, Poll, C T, Faller, T, Collingwood, S P and Danahay, H (2015) NVP-QBE170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia. British Journal of Pharmacology, 172 (11). pp. 2814-2826. ISSN 0007-1188

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Abstract

Background and Purpose
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.

Experimental Approach
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).

Key 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 and Implications
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.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Biochemistry
Research Centres and Groups:	Sussex Drug Discovery Centre
Depositing User:	Martin Gosling
Date Deposited:	15 Aug 2018 08:17
Last Modified:	09 Mar 2021 15:45
URI:	http://sro.sussex.ac.uk/id/eprint/77851

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