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

PI3K & delta; is a promising target for the treatment ofinflammatorydisease; however, the application of PI3K & delta; inhibitors in acuterespiratory inflammatory diseases is rarely investigated. In thisstudy, through scaffold hopping design, we report a new series of1H-pyrazolo[3,4-d]pyrimidin-4-amine-tethered3-methyl-1-aryl-1H-indazoles as highly selectiveand potent PI3K & delta; inhibitors with significant anti-inflammatoryactivities for treatment of acute lung injury (ALI). There were 29compounds designed, prepared, and subjected to PI3K & delta; inhibitoryactivity evaluation and anti-inflammatory activity evaluation in macrophages. ( S )-29 was identifiedas a candidate with high PI3K & delta; inhibitory activity, isoformselectivity, and high oral bioavailability. The in vivo administration of ( S )-29 at 10 mg/kg dosage could significantly ameliorate histopathologicalchanges and attenuate lung inflammation in lung tissues of LPS-challengedmice. Molecular docking demonstrated the success of scaffold hoppingdesign. Overall, ( S )-29 is a potent PI3K & delta; inhibitor which might be a promisingcandidate for the treatment of ALI.