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  3. Discovery of Novel Antiosteoporosis Leads with Bone Resorption Inhibition and Anabolic Promotion through a Chemotype-Assembly Approach

Discovery of Novel Antiosteoporosis Leads with Bone Resorption Inhibition and Anabolic Promotion through a Chemotype-Assembly Approach

  • J Med Chem. 2024 Sep 12;67(17):15311-15327. doi: 10.1021/acs.jmedchem.4c00909.
Dane Huang 1,  Chao Zhao 2 3,  Ruyue Li 4,  Nan Yao 1,  Jun Xu 2,  Qiong Gu 2
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangdong Provincial Second Hospital of Traditional Chinese Medicine (Guangdong Provincial Engineering Technology Research Institute of Traditional Chinese Medicine), Guangzhou 510095, China.
  • 2 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 3 Cell Inspire Therapeutics Co., Ltd., Shenzhen 518101, China.
  • 4 Department of Pharmacy, People's Hospital of Zhengzhou, Zhengzhou 450053, China.
PMID: 39167391 DOI: 10.1021/acs.jmedchem.4c00909
Abstract

Developing a dual-efficiency agent with antiresorptive and anabolic applications is a promising strategy for treating osteoporosis. This study reports the discovery of dual antiosteoporosis agents via a chemotype-assembly approach. Chemotype analysis identified 12 antiresorptive and 12 anabolic chemotypes and 7 dual-function chemotype-assembly rules. Based on these assembly rules, a dual-functional compound S24 was discovered. S24 exhibits osteoclastogenesis inhibition with an IC50 value of 10.28 μM and osteoblast differentiation stimulation at 10 μM. S24 derivatives were designed and synthesized based on the activity relationship of the chemotypes. This yielded a more active compound, S24-14, with an osteoclastogenesis inhibition IC50 value of 0.40 μM and osteoblast differentiation stimulation at 1.0 μM; compound S24-14 also suppressed bone loss in vivo. These results prove that S24-14 can be a potential lead for antiosteoporosis drug development.

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