Medicinal-chemistry-driven strategies for the synthesis of antiosteoclastogenic small molecules targeting RANKL and its downstream signaling pathways.

Hundreds of millions of people worldwide suffer from bone-loss disorders such as osteoporosis and rheumatoid arthritis, conditions driven by an imbalance between bone resorption and bone remodeling. The discovery of the receptor activator nuclear factor kappa-receptor activator nuclear factor kappa-osteoprotegerin (RANK-RANKL-OPG) triad as the central regulatory system for osteoclast formation (osteoclastogenesis) has provided a unifying molecular framework for therapeutic intervention. Because RANKL-induced activation of nuclear factor kappa B (NF-κB), mitogen activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) orchestrates the transcriptional program of osteoclastogenesis, selectively disrupting these signaling nodes has emerged as a powerful therapeutic strategy. The success of RANKL-inhibitors in the management of osteoclastogenesis and related bone disorders further motivated the researchers to develop more optimized small molecules with potential inhibitory effects on RANKL and its downstream signaling pathways. This review highlights different synthetic strategies with examples, applied for the synthesis of anti-osteoclast small molecules with highlights on their structure-activity relationship (SAR). Emphasis is placed on how the synthesized or derivatized compounds inhibit RANKL and its downstream signaling molecules, leading to the attenuation of osteoclastogenesis. Collectively, these strategy-driven advances outline a roadmap for the future development of safer and more effective anti-osteoclastogenic agents.