RORγt inverse agonist(Novartis)

Guided by the mode of action of 13, our previously discovered RORγt inverse agonist, we conducted five rounds of design syntheses and structure-activity relationship (SAR) studies, ultimately identifying RORγt inverse agonist 5a, which exhibited superior in vitro activity compared to 13. Besides, 5a showed promising therapeutic effects in alleviating psoriasis in mice by intraperitoneal injection. Due to the high lipophilicity and in vitro pharmacokinetic properties of 5a, it was formulated into an ointment, which enabled effective skin retention and mitigated systemic side effects. The ointment of 5a was assessed in the mouse model, where it demonstrated significant antipsoriatic effects, superior to 13 and comparable to the positive control GSK2981278, without obvious toxicity. Furthermore, we elucidated molecular mechanism of action for inverse agonist 5a and agonist 1e by means of molecular dynamics (MD) simulation. In summary, 5a holds great promise as a novel antipsoriatic drug candidate.