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

Although the advantages of sp(3)-rich, sterically complicated molecules in drug development have been pointed out, modern screening libraries are filled with planar, sp(2)-rich components. Compounds that are sp(3)-rich are difficult to synthesize, and thus we aimed to invent an efficient method to construct sp(3)-rich libraries. By modifying sp(3)-rich 7-azanorbornane scaffolds through click chemistry, we efficiently prepared a small set of compounds. These compounds were not only sp(3)-rich, but also had sufficient lead-like properties in view of molecular weights and hydrophobicity. Screening assays of this library provided weak kappa 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.