Identification of JNJ-61803534, a RORγt Inverse Agonist for the Treatment of Psoriasis

The
retinoic acid receptor-related orphan receptor gamma t (RORγt)
is a nuclear transcription factor expressed in both innate and adaptive
immune cells, driving Th17 cell differentiation and IL-17 production.
The IL-23/IL-17 pathway is implicated in autoimmune and inflammatory
diseases, and biologics that target IL-23/IL-17 signaling are efficacious
in the treatment of psoriasis and psoriatic arthritis. RORγt,
at the core of this pathway, represents an attractive opportunity
for small-molecule intervention; however, combining high potency,
nuclear receptor selectivity, and good physicochemical properties
remains a challenge for RORγt inverse agonists. Recently, thiazole
amides have been identified as potent RORγt inverse agonists;
however, they often suffer from CYP450 autoinduction in the rat, precluding
further development. Herein, we describe the discovery and development
of potent and selective thiazole bisamide RORγt inverse agonists
that avoid autoinduction in the rat. This effort culminated in the
discovery of JNJ-61803534, which advanced into phase 1 clinical trials.