JNJ-61803534 is a potent and orally active RORγt inverse agonist.
JNJ-61803534 exhibits anti-inflammatory activity. It inhibits IL-17A production in human CD4+ T cells under Th17 differentiation conditions. JNJ-61803534 (1 nM-1 μM) inhibits IL-17A, IL-17F, IFN-γ, and IL-22 production in CD4+ T cells isolated from human blood. Additionally, this compound dose-dependently suppresses the production of IL-17A, IL-17F, and IL-22 with IC50 values of 19 (14–26) nM, 22 (8–62) nM, and 27 (13–55) nM, respectively.
JNJ-61803534 inhibits RORγt transcription in HEK-293 T cells transfected with vectors encoding RORγt, with an IC50 of 9.6 nM. However, The IC50 values for RORα and RORβ were > 2 µM in similar assays.
JNJ-61803534 is an orally active and well-tolerated compound.
In in vivo pharmacokinetics pharmacodynamics study, JNJ-61803534 shows time-dependent exposures in plasma and inhibits ex vivo stimulated IL-17A production in the blood. Besides, Compound concentration for 50% inhibition of ex vivo IL-17A was between 0.24 and 0.86 µM.
In a mouse collagen-induced arthritis model, JNJ-61803534 (3-100 mg/kg BID or 60 mg/kg QD, p.o.) alleviates inflammation, cartilage damage, and bone destruction in mouse collagen-induced arthritis (CIA) model. Additionally, JNJ-61803534 decreases clinical arthritis scores and hind paw histopathology scores.
JNJ-61803534 (30 and 100 mg/kg, p.o.) alleviates Imiquimod-induced dermal psoriatic-like inflammation in mice. As a result, JNJ-61803534 significantly reduces the disease scores (thickness, redness, scaling) of back skin in a dose-dependent manner. What’s more, JNJ-61803534 significantly inhibits IMQ-induced expression of IL-17A, IL-17F, and IL-22 genes at 100 mg/kg. And it also shows a trend toward inhibition of IL-17A and IL-17F expression at 30 mg/kg and IL-23R at 30 and 100 mg/kg, respectively.
In the toxicology study, JNJ-61803534 is well tolerated and had no indications of off-target effects.
In conclusion, JNJ-61803534 is a potent and orally active RORγt inhibitor. It has the potential for psoriasis and arthritis research.
Xue X, et al. Sci Rep. 2021 May 26;11(1):11066