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

  • J Med Chem. 2023 Sep 14;66(17):11905-11926. doi: 10.1021/acs.jmedchem.3c00508.
Yongmei Tang  1 ,  Fanli Zheng  2 ,  Xiaodong Bao  1 ,  Yanan Zheng  2 ,  Xueping Hu  3 ,  Siyue Lou  2 ,  Huajun Zhao  2 ,  Sunliang Cui  1
Affiliations
  • 1. Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2. College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311402, China.
  • 3. Institute of Molecular Sciences and Engineering, Institute of Frontier and Interdisciplinary Science, Shandong University, Qingdao 266237, China.
PMID: 37606563 DOI: 10.1021/acs.jmedchem.3c00508
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.

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