Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis
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, <b>D4</b> 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. <b>(</b><i>R</i><b>)-D4</b>, the eutomer of <b>D4</b>, matched or exceeded GSK2981278's therapeutic effects at lower doses, with no adverse effects observed after 2 weeks of administration. These results position <b>(</b><i>R</i><b>)-D4</b> as a promising and orally bioavailable candidate for Th17-mediated autoimmune disease treatment.
Authors
- Qing-Xin Wang
- Hongjiang Xu (ORCID: https://orcid.org/0009-0008-1626-4867)
- Xiaofang Zou (ORCID: https://orcid.org/0000-0003-1287-6192)
- Xuejiao Leng
- Jian Zhou (ORCID: https://orcid.org/0000-0002-1534-2279)
- Shan‐Liang Sun (ORCID: https://orcid.org/0000-0001-7011-6146)
- Wei‐Chen Dai
- Jiazhen Wu (ORCID: https://orcid.org/0000-0002-6417-8495)
- Nian‐Guang Li
- Yan‐Cheng Yu (ORCID: https://orcid.org/0000-0002-9783-775X)
- Xueqin Ma (ORCID: https://orcid.org/0000-0003-4818-5967)
- Xiaolong Jiang (ORCID: https://orcid.org/0000-0001-8066-1383)
- Xiayun Chang
- Wei Song (ORCID: https://orcid.org/0000-0002-6136-0400)
- Zhen‐Jiang Tong
- Shao‐Peng Yu
- Zhi‐Hao Shi (ORCID: https://orcid.org/0000-0002-6827-9533)
- Shi-Han Wu
- Yibo Wang (ORCID: https://orcid.org/0000-0001-9984-581X)
- Zixuan Wang (ORCID: https://orcid.org/0009-0007-8289-1538)
- Qingqing Li (ORCID: https://orcid.org/0000-0003-3043-921X)
- Jiao Cai
- Yun Zhou (ORCID: https://orcid.org/0000-0002-7466-4593)
- Xin Xue (ORCID: https://orcid.org/0000-0001-6143-2921)
- Jin Yang (ORCID: https://orcid.org/0000-0002-5337-487X)
- Ning Ding (ORCID: https://orcid.org/0000-0002-2729-6126)
- Tian‐Hua Wei
- Xiaojin Wang
- Wei Shi (ORCID: https://orcid.org/0009-0004-5305-4130)
Institutions
- Nanjing University of Chinese Medicine (CN)
- China Pharmaceutical University (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01727
- Citations
- 1
- Primary Topic
- Synthesis and biological activity
- Type
- article
- Field-Weighted Citation Impact
- 0.25
Funders
- Government of Jiangsu Province
- Major Research Plan