A number of RORγ inhibitors have been reported
over the past
decade. There were also several examples advancing to human clinical
trials, however, none of them has reached the market yet, suggesting
that there could be common obstacles for their future development.
As was expected from the general homology of nuclear receptor ligands,
insufficient selectivity as well as poor physicochemical properties
were identified as potential risks for a RORγ program. Based
on such considerations, we conducted a SAR investigation by prioritizing
drug-like properties to mitigate such potential drawbacks. After an
intensive SAR exploration with strong emphasis on “drug-likeness”
indices, an orally available RORγ inhibitor, JTE-151, was finally
generated and was advanced to a human clinical trial. The compound
was confirmed to possess highly selective profiles along with good
metabolic stability, and most beneficially, no serious adverse events
(SAE) and good PK profiles were observed in the human clinical trial.