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

Abstract

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 bypass 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.

Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation

“…Moreover, in the context of chronic lung inflammation, administration by inhalation can guarantee a direct delivery of the drug to the site of action, resulting in a rapid onset of the pharmacological effect and, at the same time, a potential reduction of systemic side effects. Encouraged by preclinical evidence from internal research and by literature data, − we focused our discovery project on the design of novel lung-restricted inhibitors, selective for the PI3Kδ isoform.…”

“…Remarkably, PI3Kδ-selective or dual PI3Kδ/γ modulators have been successfully progressed to clinical stages as inhalation treatments for chronic lung diseases (e.g., Nemiralisib, GSK2292767, RV1729, RV6153, and AZD8154, Figure ). − …”