Application of an “inhalation by design” approach to the identification and in-vitro evaluation of novel purine based PI3Kδ inhibitors

PI3Kδ is a lipid kinase which plays a key role in airway inflammatory conditions. Accordingly, the inhibition of PI3Kδ can be considered a valuable strategy for the treatment of chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD). In this work, we describe our efforts to identify new PI3Kδ inhibitors following an "inhalation by design" strategy. Starting from the identification of a purine scaffold, we carried out a preliminary SAR expansion which led to the identification of a new hit characterized by a high enzymatic potency and moderate PI3Kδ selectivity. A subsequent optimization led to novel purine based derivatives with favorable in vitro ADME profiles, which might represent promising starting points for future development of new inhaled drug candidates.