Advances in the Discovery of Novel Inhaled PI3Kδ Inhibitors for the Treatment of Asthma.

Bronchial asthma is the most common chronic respiratory illness, the incidence of which continues to increase annually. Currently, effective treatments for CS-resistant asthma and severe asthma are still lacking, and new therapeutic regimens are urgently required. PI3Kδ is a key enzyme in hematopoietic cells and represents a major target for oncology and inflammatory disease (particularly respiratory disease, asthma and COPD). In the case of respiratory disease, the ability to inhibit PI3Kδ in the lungs shows a higher safety and therapeutic index relative to systemic inhibition. In recent years, paradigm shifts have occurred in inhalation therapeutics for systemic and topical drug delivery due to the favorable properties of lungs, including their large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including a non-invasive route of administration, low metabolic activity, a controlled environment for systemic absorption and the ability to avoid first bypassing metabolism. In this review, we focus on the discovery and development of inhaled drugs targeting PI3Kδ for asthma by focusing on their activity and selectivity, in addition to their potential in drug design strategies using inhaled administration.