Discovery of Novel Antiosteoporosis Leads with Bone Resorption Inhibition and Anabolic Promotion through a Chemotype-Assembly Approach

Developing a dual-efficiency agent with antiresorptive and anabolic applications is a promising strategy for treating osteoporosis. This study reports the discovery of dual antiosteoporosis agents <i>via</i> a chemotype-assembly approach. Chemotype analysis identified 12 antiresorptive and 12 anabolic chemotypes and 7 dual-function chemotype-assembly rules. Based on these assembly rules, a dual-functional compound <b>S24</b> was discovered. <b>S24</b> exhibits osteoclastogenesis inhibition with an IC₅₀ value of 10.28 μM and osteoblast differentiation stimulation at 10 μM. <b>S24</b> derivatives were designed and synthesized based on the activity relationship of the chemotypes. This yielded a more active compound, <b>S24-14</b>, with an osteoclastogenesis inhibition IC₅₀ value of 0.40 μM and osteoblast differentiation stimulation at 1.0 μM; compound <b>S24-14</b> also suppressed bone loss <i>in vivo</i>. These results prove that <b>S24-14</b> can be a potential lead for antiosteoporosis drug development.