TY - JOUR
T1 - Synthesis and Biological Evaluation of Heterocycle-Fused Pyxinol Derivatives as Anti-osteoporosis Agents
AU - Zhang, De Jie
AU - Yue, Yan Xin
AU - Zhang, Yu Xin
AU - Xu, Long Yu
AU - Ning, Ruo Nan
AU - Jiang, Min
AU - Qiu, Wen Wei
PY - 2025/12/11
Y1 - 2025/12/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105024730851
U2 - 10.1021/acs.jmedchem.5c02212
DO - 10.1021/acs.jmedchem.5c02212
M3 - 文章
C2 - 41329086
AN - SCOPUS:105024730851
SN - 0022-2623
VL - 68
SP - 25229
EP - 25254
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 23
ER -