A Concise and Modular Approach to Generate Novel RORγ Agonists

A variety of RORγ inhibitors have been identified, including clinical compounds such as VTP-43742 and JTE-151. In contrast, RORγ agonists have been less explored and LYC-55716 is, to the best of our knowledge, the sole example reached a human clinical investigation. To generate a novel RORγ agonist, functionality switching from preceding RORγ inhibitors has been considered as a rational strategy. Such reported earlier attempts have been hampered by a loss of physicochemical properties to elevated lipophilicity. Starting from RORγ inhibitors, corresponding agonists were generated virtually to assess their druglike characters. Based on their ligand efficiency and lipophilicity, a cyclic amine carboxylate core was regarded as the best for maintaining favorable physicochemical properties. This scaffold was subjected to final optimization by attaching function-oriented modules retaining druglike properties. After multiparameter optimization, novel selective RORγ agonists were discovered, and their <i>in vivo</i> effects were confirmed in a syngeneic mouse model after oral administration.