BI 1265162 is an inhaled epithelial sodium channel (ENaC) inhibitor that reached clinical phase 2. This talk will discuss different approaches to achieve lung tissue selective ENaC inhibition and present how the structure of BI 1265162 evolved from a literature starting point. Besides the need for a long duration of action without renal side effects, physicochemical properties required for administration via the Respimat® Soft Mist™ inhaler guided our compound optimization.BI 1265162 contains a phosphine oxide moiety, and the properties brought in by this less common structural element are discussed.