化学
过氧化物酶体增殖物激活受体
体内
对抗
骨质疏松症
受体
药理学
过氧化物酶体
立体化学
生物化学
内科学
生物
生物技术
医学
作者
Xing Peng,Zhikang Zhang,Yuting Zhang,Huihao Zhou,Wenqi Li,Minxian Dai,Judie Shang,Jun Xu,Qiong Gu
标识
DOI:10.1021/acs.jmedchem.4c01377
摘要
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 (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 (KD = 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI