Artificial Intelligence-Driven Discovery of Pyrazolo[1,5- a]pyrimidine Derivatives as Novel Phosphodiesterase 4 Inhibitors for Treating Idiopathic Pulmonary Fibrosis

  • J Med Chem. 2025 Nov 27;68(22):24436-24455. doi: 10.1021/acs.jmedchem.5c02407.
Zheng Li  1  2 ,  Wanting Huan  1 ,  Xingfu Liu  1 ,  Kai Zhang  1  2 ,  Xue Wang  1 ,  Yiyou Huang  1 ,  Qian Zhou  1 ,  Shuheng Huang  1 ,  Zhipei Sang  1 ,  Hai-Bin Luo  1  3
Affiliations
  • 1. Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 2. School of Life and Health Science, Hainan University, Haikou 570228, China.
  • 3. Song Li's Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya 572000, China.
PMID: 41252469 DOI: 10.1021/acs.jmedchem.5c02407
Abstract

Phosphodiesterase 4 (PDE4) has been validated as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF), a devastating interstitial lung disease lacking really effective therapeutic drugs, particularly exacerbated in the post-COVID-19 era. Herein, we reported the discovery of 13c, a novel pyrazolo[1,5-a]pyrimidine-based PDE4 Inhibitor, via an innovative artificial intelligence (AI)-driven virtual screening approach integrated with structure-based design. The cocrystal analysis of PDE4-13c elucidated the structural basis of its high affinity, revealing that the unique "halogen-binding and metal-coordination" synergistic network significantly influenced PDE4 inhibitory activity, which resulted in a 268-fold potency enhancement (IC50 = 2.7 nM) over hit T3700 (IC50 = 725 nM). Notably, 13c exhibited remarkable hepatic microsomal stability (RLM1/2 = 141.4 min). Furthermore, 13c exhibited remarkable antifibrotic activity in vitro and significantly attenuated bleomycin-induced pulmonary fibrosis in vivo, highlighting its potential as a novel PDE4 Inhibitor for IPF.

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