1. Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis.
- Author
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Sun SL, Xu HJ, Jiang XL, Zhou J, Shi W, Wang XJ, Song W, Chang XY, Ma XQ, Zou XF, Wu SH, Yang J, Li QQ, Wang ZX, Cai J, Yu SP, Wang QX, Wei TH, Wu JZ, Tong ZJ, Zhou Y, Wang YB, Yu YC, Leng XJ, Ding N, Shi ZH, Dai WC, Xue X, Li NG, and Wang XL
- Subjects
- Animals, Mice, Rats, Administration, Oral, Humans, Male, Drug Inverse Agonism, Structure-Activity Relationship, Drug Discovery, Rats, Sprague-Dawley, Female, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Quinolines pharmacokinetics, Quinolines pharmacology, Quinolines chemistry, Quinolines therapeutic use, Quinolines chemical synthesis, Biological Availability, Arthritis, Rheumatoid drug therapy
- Abstract
The retinoic acid receptor-related orphan receptor γt (RORγt) is a key regulator of Th17 cells, associated with autoimmune diseases, making it a significant drug target. Herein, we designed and synthesized 1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline derivatives, improving upon GSK2981278 to enhance bioavailability. Of which, D4 exhibited superior bioavailability (F = 48.1 and 32.9% in mice and rats, respectively) compared to GSK2981278 (F = 6.2 and 4.1%, respectively), and effectively treated psoriasis in mice at lower doses. Moreover, for the first time, we report the efficacies of a RORγt inverse agonist in mouse models of rheumatoid arthritis. ( R )-D4 , the eutomer of D4 , matched or exceeded GSK2981278's therapeutic effects at lower doses, with no adverse effects observed after 2 weeks of administration. These results position ( R )-D4 as a promising and orally bioavailable candidate for Th17-mediated autoimmune disease treatment.
- Published
- 2024
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