2. Academic Validation
  3. Synthesis of Heterocyclic Ring-Fused Bisnoralcohol Derivatives as Novel Small-Molecule Antiosteoporosis Agents

Synthesis of Heterocyclic Ring-Fused Bisnoralcohol Derivatives as Novel Small-Molecule Antiosteoporosis Agents

  • J Med Chem. 2024 May 23;67(10):8271-8295. doi: 10.1021/acs.jmedchem.4c00349.
De-Jie Zhang 1,  Rong Chen 1,  Yu-Xin Zhang 2,  Chen-Chen Li 1,  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, Shanghai 200025, China.
PMID: 38717088 DOI: 10.1021/acs.jmedchem.4c00349
Abstract

A series of heterocyclic ring-fused derivatives of bisnoralcohol (BA) were synthesized and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Most of these derivatives possessed potent antiosteoporosis activities in a dose-dependent manner. Among these compounds, 31 (SH442, IC50 = 0.052 μM) exhibited the highest potency, displaying 100% inhibition at 1.0 μM and 82.8% inhibition at an even lower concentration of 0.1 μM, which was much more potent than the lead compound BA (IC50 = 2.325 μM). Cytotoxicity tests suggested that the inhibitory effect of these compounds on RANKL-induced osteoclast differentiation did not result from their cytotoxicity. Mechanistic studies revealed that SH442 inhibited the expression of osteoclastogenesis-related marker genes and proteins, including TRAP, TRAF6, c-Fos, CTSK, and MMP9. Especially, SH442 could significantly attenuate bone loss of ovariectomy mouse in vivo. Therefore, these BA derivatives could be used as promising leads for the development of a new type of antiosteoporosis agent.

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