Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury

Abstract

PI3Kδ is a promising target for the treatment of inflammatory disease; however, the application of PI3Kδ inhibitors in acute respiratory inflammatory diseases is rarely investigated. In this study, through scaffold hopping design, we report a new series of 1H-pyrazolo­[3,4-d]­pyrimidin-4-amine-tethered 3-methyl-1-aryl-1H-indazoles as highly selective and potent PI3Kδ inhibitors with significant anti-inflammatory activities for treatment of acute lung injury (ALI). There were 29 compounds designed, prepared, and subjected to PI3Kδ inhibitory activity evaluation and anti-inflammatory activity evaluation in macrophages. ( S )-29 was identified as a candidate with high PI3Kδ inhibitory activity, isoform selectivity, and high oral bioavailability. The in vivo administration of ( S )-29 at 10 mg/kg dosage could significantly ameliorate histopathological changes and attenuate lung inflammation in lung tissues of LPS-challenged mice. Molecular docking demonstrated the success of scaffold hopping design. Overall, ( S )-29 is a potent PI3Kδ inhibitor which might be a promising candidate for the treatment of ALI.

Discovery of Novel Azaindoles as Potent and Selective PI3Kδ Inhibitors for Treatment of Multiple Sclerosis

“…The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under vacuum to obtain the residue, which was purified by silica gel column chromatography to afford 27−53. ( ( ( (35) ( (36) ( (…”

“…Typically, PI3Kδ is mainly expressed in the hematopoietic system and has been considered as a high-value target for the treatment of inflammation and autoimmune disease, , while several PI3Kδ inhibitors have been investigated for the treatment of chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis (RA). − Since PI3Kδ is highly related to T-cell function, it is reasonable to explore the PI3Kδ inhibitor in MS therapy, but this research is relatively scarce . In continuation of our interests in PI3Kδ inhibitor development, − herein, we would like to report a discovery of novel azaindoles as potent and selective PI3Kδ inhibitors for treatment of multiple sclerosis (Figure B).…”

Design and Synthesis of Indazole–Indole Hybrid via tert-Butyl Nitrite Mediated Cascade Diazotization/Isomerization/Cyclization

“…Among them, indazole and indole are privileged scaffolds in the fields of drug discovery and material chemistry. For example, the indazole scaffold possesses a wide range of pharmacological activities, such as treatment of respiratory disease, central nervous system (CNS) disorders, Parkinson’s disease, and multikinase inhibitory activities . These important and broad-spectrum activities have inspired synthetic chemists to continue to develop new methods for the synthesis of functionalized indazoles .…”