AZD5634

Inhibitor of the amiloride-sensitive Epithelial Sodium Channel (ENaC)


Preclinical Pharmacology

AZD5634 is a potent inhibitor of the epithelial sodium channel in human, sheep and rat in vitro with an IC50 of 3.8 nmol/L for the human ENaC. AZD5634 is designed to have a long duration at the target and at the apical side of the airways. Thus, its inhibitory effects at ENaC are long lasting. Its effects at the NHE-channels have not been explored.

In preclinical studies including pivotal 14D GLP repeat dose (aqueous) inhaled toxicity studies in rats and dogs AZD5634 was well tolerated. In addition, 4- day and 35- day non-GLP dose-finding studies in rat have been performed and three DRF studies in dogs with no safety alerts. Two of the dog studies included intravenous administration to increase systemic exposures (NOAEL for this study was 0.480 mg/kg/day with a supplementary daily I.V dose of 6.6 µg/kg/day). Transient salivation and coughing was observed in the dogs at higher exposures. 3 Month repeat dose tox studies in rat and dog showed good tolerability with a NOAEL of 3.42 mg/kg in rats and 0.422 mg/kg (+10 µg/kg iv top up) in dogs.


Suitable for and exclusions

AZD5634 is suitable for both preclinical and clinical research when selective and potent ENaC inhibition is required. The compound is light sensitive, but otherwise stable and easily formulated at slightly acidic pH. The compound stays at the target for an extended time frame (>24h) and we do not encourage washout and reuse of, for example, preclinical tissues


Additional Information


Clinical Trials

Clinical trials: NCT02950805 NCT02679729


Publications

Giordetti et al 2020 (submitted to BJP Oct 2020), Ermund et al NACFC 2017, Lewis et al NACFC 2018


Initial Indication

Cystic Fibrosis, COPD


Route of administration

Inhaled/IV/topical