2. Academic Validation
  3. Synthesis and Biological Evaluation of C-17-Amino-Substituted Pyrazole-Fused Betulinic Acid Derivatives as Novel Agents for Osteoarthritis Treatment

Synthesis and Biological Evaluation of C-17-Amino-Substituted Pyrazole-Fused Betulinic Acid Derivatives as Novel Agents for Osteoarthritis Treatment

  • J Med Chem. 2021 Sep 23;64(18):13676-13692. doi: 10.1021/acs.jmedchem.1c01019.
Jie Wang 1 2,  Wenhui Wei 3 2,  Xiaofei Zhang 1,  Shiqi Cao 3 2,  Bintao Hu 2 4,  Yang Ye 2 4,  Min Jiang 5,  Tianqi Wang 5,  Jianping Zuo 3 2,  Shijun He 3 2,  Chunhao Yang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 State Key Laboratory of Drug Research, Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 4 State Key Laboratory of Drug Research, Natural Products Chemistry Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Second Ruijin Road, Shanghai 200025, China.
PMID: 34491054 DOI: 10.1021/acs.jmedchem.1c01019
Abstract

A series of pyrazole-fused betulinic acid (BA) derivatives were designed and synthesized by replacing the carboxyl group at C-17 with aliphatic amine, amide, and urea groups. The suppressive effects of the compounds on osteoclast (OC) formation and inflammatory cytokine production were evaluated on murine macrophages, RAW264.7 cells, conditioned with receptor activator for nuclear factor-κB ligand (RANKL)/macrophage colony stimulating factor (M-CSF) or lipopolysaccharide (LPS), respectively. Results showed that, compared with betulinic acid, most of these compounds exhibited significant improvements in inhibitory potency. Compound 25 exhibited distinguished activities on inhibiting OC differentiation with an IC50 value of 1.86 μM. Meanwhile, compound 25, displaying the most promising suppression on IL-1β secretion from RAW264.7 cells, was further found to possess therapeutic effects in the sodium monoiodoacetate (MIA)-induced osteoarthritis rat model. Dose-dependent benefits were observed in MIA-elicited rats with ameliorated joint pain as well as decreased cartilage damage and bone changes after compound 25 treatment.

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