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 via 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 S24 was discovered. S24 exhibits osteoclastogenesis
inhibition with an IC50 value of 10.28 μM and osteoblast
differentiation stimulation at 10 μM. S24 derivatives
were designed and synthesized based on the activity relationship of
the chemotypes. This yielded a more active compound, S24–14, with an osteoclastogenesis inhibition IC50 value of
0.40 μM and osteoblast differentiation stimulation at 1.0 μM;
compound S24–14 also suppressed bone loss in vivo. These results prove that S24–14 can be a potential lead for antiosteoporosis drug development.