Discovery of Novel Neo -Clerodane Derivatives as Potent Dual-Functional Antiosteoporosis Agents through Targeting Peroxisome Proliferator-Activated Receptor-γ

A library of 31 natural -clerodanes isolated from was assayed for antiosteoporosis. This results in 18 -clerodane osteoclastogenesis inhibitors, and compound prevents bone loss in vivo. Further mechanistic studies demonstrated that these compounds inhibit osteoporosis by antagonizing peroxisome proliferator-activated receptor-γ (PPARγ). We designed and synthesized 17 compounds by chemically modifying the natural -clerodane (highly potent and the major composition of extract) by means of structure-based drug design techniques. Among these -clerodane derivatives, compound is the most potent osteoporosis inhibitor with a 46-fold improvement in inhibiting osteoclastogenesis (IC = 0.042 vs 1.92 μM), 11-fold increased activity in PPARγ antagonism (EC = 0.75 vs 8.35 μM), 66-fold enhancement in receptor affinity ( = 0.27 vs 17.7 μM), and enhanced osteogenic promotion compared to . This underscores the potential of -clerodane diterpenoids as promising leads for osteoporosis treatment by targeting PPARγ.