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 in vivo effects were confirmed in a syngeneic mouse model
after oral administration.