Discovery of Novel <i>N</i>-Sulfonamide-tetrahydroquinolines as Potent Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists for the Treatment of Psoriasis

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