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

A library of 31 natural neo -clerodanes isolated from Ajuga decumbens was assayed for antiosteoporosis. This results in 18 neo -clerodane osteoclastogenesis inhibitors, and compound 3 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 neo -clerodane 19 (highly potent and the major composition of A. decumbens extract) by means of structure-based drug design techniques. Among these neo -clerodane derivatives, compound 34 is the most potent osteoporosis inhibitor with a 46-fold improvement in inhibiting osteoclastogenesis (IC 50 = 0.042 vs 1.92 μM), 11-fold increased activity in PPARγ antagonism (EC 50 = 0.75 vs 8.35 μM), 66-fold enhancement in receptor affinity ( K D = 0.27 vs 17.7 μM), and enhanced osteogenic promotion compared to 19 . This underscores the potential of neo -clerodane diterpenoids as promising leads for osteoporosis treatment by targeting PPARγ.