Epithelial Na ⁺ Channel Inhibitors for the Treatment of Cystic Fibrosis

Abstract

The epithelial Na channel (ENaC) is a key regulator of the volume of airway surface liquid (ASL) and is found in the human airway epithelium. In cystic fibrosis (CF), Na hyperabsorption through ENaC, in the absence of cystic fibrosis transmembrane conductance regulator mediated anion secretion, results in the dehydration of respiratory secretions and the impairment of mucociliary clearance. The hypothesis of utilizing an ENaC blocking molecule to facilitate restoration of the airway surface liquid volume sufficiently to allow normal mucociliary clearance is of interest in the management of lung disease in CF patients. This review summarizes the published patent applications from 2014 to the end of 2016 that claim approaches to inhibit the function of ENaC for the treatment of CF.

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

“…Previous reviews have discussed in detail, prior unsuccessful attempts at inhibiting ENaC [30–33], although they continue to inform current efforts; Table 1 summarizes these previous ENaC studies. Briefly, the development of the small molecule ENaC inhibitor amiloride marked the first attempt at the therapeutic use of ENaC inhibition in CF [37–40].…”

“…Table 2 summarizes these compounds which are currently in development. Many of these compounds share characteristics which distinguish them from previous drugs targeting ENaC (structures available in [33]). In particular, these compounds are intended to exhibit higher specificity to the airway epithelium, while minimizing systemic exposure and off-target effects, while retaining a similar or higher degree of efficacy.…”

“…BI 443651 is another small molecule ENaC inhibitor currently in development by Boehringer Ingelheim. Boehringer Ingelheim has been developing compounds with potent ENaC activity for recently, with several patent application filings in the past 5 years [33]. Presently, their candidate molecule BI 443651 is undergoing phase 1 clinical trials in CF patients, with recruitment ongoing (NCT02976519).A separatephase1clinicaltrialofBI 443651 in patients with mild asthma recently completed, with results pending (NCT03135899).…”

“…These patients possessing rare SCNN1D mutations also demonstrated a long-term nonprogressive phenotype in lung function in which their lung function over a period of more than 20 years experienced minimal changes lending further support that ENaC is a plausible therapeutic target [17]. Thus, ENaC has been proposed as a putative target to partially ameliorate the mucus dehydration which is commonly observed in the CF population [30–33]. This therapeutic strategy is particularly enticing because it operates independent of CFTR function and CFTR mutation class [34,35].…”

Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

“…In this work, we focus on the cross-talk between two crucial regulators of ENaC: the extracellular short palate lung and nasal epithelial clone 1 (SPLUNC1) protein and phosphatidylinositol 4,5-biphosphate (PI(4,5)P 2 ). Distinct parallel mechanisms of ENaC regulation have been investigated [9,10], and several models of airway surface liquid (ASL) and ENaC regulation and their impact on ion-driven water fluxes have been proposed [11][12][13][14][15][16]. However, these models do not account for the synergistic regulation of ENaC and ASL by SPLUNC1 and PI(4,5)P 2 .…”