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

A library of 31 natural <i>neo</i>-clerodanes isolated from <i>Ajuga decumbens</i> was assayed for antiosteoporosis. This results in 18 <i>neo</i>-clerodane osteoclastogenesis inhibitors, and compound <b>3</b> 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 <i>neo</i>-clerodane <b>19</b> (highly potent and the major composition of <i>A. decumbens</i> extract) by means of structure-based drug design techniques. Among these <i>neo</i>-clerodane derivatives, compound <b>34</b> is the most potent osteoporosis inhibitor with a 46-fold improvement in inhibiting osteoclastogenesis (IC₅₀ = 0.042 vs 1.92 μM), 11-fold increased activity in PPARγ antagonism (EC₅₀ = 0.75 vs 8.35 μM), 66-fold enhancement in receptor affinity (<i>K</i>_D = 0.27 vs 17.7 μM), and enhanced osteogenic promotion compared to <b>19</b>. This underscores the potential of <i>neo</i>-clerodane diterpenoids as promising leads for osteoporosis treatment by targeting PPARγ.