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.