Discovery and development of BI 1265162, an ENaC inhibitor for the treatment of cystic fibrosis.

Lung selective inhibition of the endothelial sodium channel (ENaC) is a potential mutation agnostic treatment of Cystic Fibrosis (CF). We describe the discovery and development of BI 1265162, the first ENaC inhibitor devoid of the amiloride structural motif that entered clinical trials. The design of BI 1265162 focused on its suitability for inhalation via the Respimat® Soft Mist™ Inhaler and a long duration of action.

A C-glycosidation approach to the central core of amphidinol 3: synthesis of the c39-c52 fragment.

[reaction: see text] A concise route to an advance precursor (3) of the central core of amphidinol 3, a natural occurring polyketide, has been developed by applying a reductive lithiation as key step. The origin of the diastereoselectivity of this reaction was comprehensively studied for nucleophilic C-glycoside donor 5 and differently protected analogues.