Discovery of\nNovel Antiosteoporosis Leads with Bone\nResorption Inhibition and Anabolic Promotion through a Chemotype-Assembly\nApproach

Developing a dual-efficiency agent\nwith antiresorptive\nand anabolic\napplications is a promising strategy for treating osteoporosis. This\nstudy reports the discovery of dual antiosteoporosis agents <i>via</i> a chemotype-assembly approach. Chemotype analysis identified\n12 antiresorptive and 12 anabolic chemotypes and 7 dual-function chemotype-assembly\nrules. Based on these assembly rules, a dual-functional compound <b>S24</b> was discovered. <b>S24</b> exhibits osteoclastogenesis\ninhibition with an IC<sub>50</sub> value of 10.28 μM and osteoblast\ndifferentiation stimulation at 10 μM. <b>S24</b> derivatives\nwere designed and synthesized based on the activity relationship of\nthe chemotypes. This yielded a more active compound, <b>S24–14</b>, with an osteoclastogenesis inhibition IC<sub>50</sub> value of\n0.40 μM and osteoblast differentiation stimulation at 1.0 μM;\ncompound <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.