Recently, Professor Wei Fu’s team from the School of Pharmacy at Fudan University published a research paper titled “Discovery of Novel N-Sulfonamide-tetrahydroquinolines as Potent Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists for the Treatment of Psoriasis” in Journal of Medicinal Chemistry. Through five rounds of structure-activity relationship (SAR) analysis, a novel RORγt inverse agonist, compound 5a, was successfully identified, which demonstrated promising therapeutic effects in a mouse model of psoriasis.
Psoriasis is an immune-mediated chronic inflammatory skin disease. Studies have shown that interleukin-17 (IL-17) plays a crucial role in the pathogenesis of psoriasis, and RORγt functions as a transcription factor that regulates the transcription of IL-17-related genes. Therefore, targeting RORγt with inverse agonists represents a promising therapeutic strategy for psoriasis.
Professor Wei Fu’s team conducted five rounds of in-depth SAR studies, resulting in the design and synthesis of a series of N-sulfonamide-tetrahydroquinoline compounds. Among them, compound 5a was found to exhibit significant in vitro activity. 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 resulting from blood entry. The ointment of 5a was further assessed in the mouse model, where it demonstrated significant anti-psoriatic effects, comparable to the positive control GSK2981278. Moreover, no acute toxicity or hERG toxicity was observed for compound 5a. The study also elucidated the binding mode and molecular mechanism of action of 5a by means of molecular docking and molecular dynamics simulations, revealing that 5a exerts its inverse agonistic effect by influencing the structure and function of RORγt. The work provides an excellent candidate for the development of novel anti-psoriatic drugs.
The co-first authors are Lunan Lv (class of 2023, MSc) and Baiyu Chen (class of 2022, PhD), with Professor Wei Fu as the corresponding author. The work is supported by grants from the National Natural Science Foundation of China and the Shanghai Science and Technology Development Foundation.
Original Link: https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02318
