2. Academic Validation
  3. Synthesis and Biological Evaluation of Heterocycle-Fused Pyxinol Derivatives as Anti-osteoporosis Agents

Synthesis and Biological Evaluation of Heterocycle-Fused Pyxinol Derivatives as Anti-osteoporosis Agents

  • J Med Chem. 2025 Dec 11;68(23):25229-25254. doi: 10.1021/acs.jmedchem.5c02212.
De-Jie Zhang 1,  Yan-Xin Yue 1,  Yu-Xin Zhang 2,  Long-Yu Xu 3,  Ruo-Nan Ning 2,  Min Jiang 2,  Wen-Wei Qiu 1
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • 2 Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine,197 Ruijin Second Road, 200025 Shanghai, China.
  • 3 Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai 200025, China.
PMID: 41329086 DOI: 10.1021/acs.jmedchem.5c02212
Abstract

A series of novel heterocycle-fused pyxinol compounds was designed and synthesized through structure-activity relationship (SAR)-guided optimization to develop potent inhibitors of RANKL-induced osteoclastogenesis. Among the synthesized derivatives, compound 36 (SH543) demonstrated the most potent inhibitory activity with an IC50 value of 3.3 nM, representing an approximately 848-fold increase in potency compared to the hit compound pyxinol (IC50 = 2.8 μM). Mechanistic investigations revealed that SH543 effectively downregulated key osteoclastogenesis-related marker genes (Atp6v0d2, Trap, Ctsk, Mmp9) and proteins (TRAP, CTSK, and MMP9). Furthermore, SH543 directly bound to KEAP1, activated the Nrf2-HO-1 antioxidant pathway, reduced ROS levels, and inhibited PI3K-AKT and MAPK signaling pathways. In ovariectomized mice, SH543 administration significantly attenuated pathological bone loss by preserving trabecular microarchitecture and improving biomechanical strength. These results establish SH543 as a promising lead compound for the development of novel antiosteoporosis agents, acting through multiple mechanisms.

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