A New Lead Identification Strategy: Screening an sp3‐rich and Lead‐like Compound Library Composed of 7‐Azanorbornane Derivatives

Although the advantages of sp3‐rich, sterically complicated molecules in drug development have been pointed out, modern screening libraries are filled with planar, sp2‐rich components. Compounds that are sp3‐rich are difficult to synthesize, and thus we aimed to invent an efficient method to construct sp3‐rich libraries. By modifying sp3‐rich 7‐azanorbornane scaffolds through click chemistry, we efficiently prepared a small set of compounds. These compounds were not only sp3‐rich, but also had sufficient “lead‐like” properties in view of molecular weights and hydrophobicity. Screening assays of this library provided weak κ opioid receptor agonists and growth hormone secretagogue receptor agonists with high hit rates. These results indicate that the 7‐azanorbornane scaffold may be a “privileged structure” for lead identification in drug discovery. Privileged structure for hits: Despite the significance of sp3‐hybridized carbons in today's medicinal chemistry, modern screening libraries are lacking in sp3‐rich components. Herein we propose a novel and efficient strategy to construct an sp3‐rich library with “lead‐like” properties. By modifying the sp3‐rich 7‐azanorbornane scaffold through click chemistry, we prepared a small‐sized library. Screening for some receptors furnished several bioactive agents with high hit rates.