Synthesis and Biological Evaluation of Novel Piperidine-3-Carboxamide Derivatives as Anti-Osteoporosis Agents Targeting Cathepsin K

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 17; p. 4011
• Main Authors: Wang, Yali, Guan, Ting, Xiong, Hegen, Hu, Wenxin, Zhu, Xianjian, Ma, Yuanyuan, Zhang, Zhiqing
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24-08-2024
• Subjects: Animals; anti-osteoporosis; Bone Density - drug effects; Bone Resorption - drug therapy; Cathepsin K - antagonists & inhibitors; Cathepsin K - metabolism; cathepsin K inhibitors; Cell culture; Collagen; Drug dosages; Enzymes; Female; Humans; Hydrocarbons; Hydrogen bonds; Mice; Molecular Docking Simulation; Molecular Structure; Older people; Osteoporosis; Osteoporosis - drug therapy; Osteoporosis - metabolism; Peptides; piperidamide-3-carboxamide derivatives; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; RANK Ligand - metabolism; RAW 264.7 Cells; Structure-Activity Relationship; synthesis; synthesis; anti-osteoporosis; cathepsin K inhibitors; piperidamide-3-carboxamide derivatives
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29174011

A series of novel piperidamide-3-carboxamide derivatives were synthesized and evaluated for their inhibitory activities against cathepsin K. Among these derivatives, compound
exhibited the most potent inhibition, with an IC
value of 0.08 µM. Molecular docking studies revealed that
formed several hydrogen bonds and hydrophobic interactions with key active-site residues of cathepsin K. In vitro,
demonstrated anti-bone resorption effects that were comparable to those of MIV-711, a cathepsin K inhibitor currently in phase 2a clinical trials for the treatment of bone metabolic disease. Western blot analysis confirmed that
effectively downregulated cathepsin K expression in RANKL-reduced RAW264.7 cells. Moreover, in vivo experiments showed that
increased the bone mineral density of OVX-induced osteoporosis mice. These results suggest that
is a potent anti-bone resorption agent targeting cathepsin K and warrants further investigation for its potential anti-osteoporosis values.