2. Academic Validation
  3. Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis

Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis

  • J Med Chem. 2024 Nov 28;67(22):20315-20342. doi: 10.1021/acs.jmedchem.4c01727.
Shan-Liang Sun 1,  Hong-Jiang Xu 2,  Xiao-Long Jiang 3,  Jian Zhou 3,  Wei Shi 2,  Xiao-Jin Wang 2,  Wei Song 2,  Xia-Yun Chang 2,  Xue-Qin Ma 2,  Xiao-Fang Zou 2,  Shi-Han Wu 1,  Jin Yang 1,  Qing-Qing Li 1,  Zi-Xuan Wang 1,  Jiao Cai 1,  Shao-Peng Yu 4,  Qing-Xin Wang 1,  Tian-Hua Wei 1,  Jia-Zhen Wu 1,  Zhen-Jiang Tong 1,  Yun Zhou 1,  Yi-Bo Wang 1,  Yan-Cheng Yu 1,  Xue-Jiao Leng 1,  Ning Ding 1,  Zhi-Hao Shi 5,  Wei-Chen Dai 1,  Xin Xue 1,  Nian-Guang Li 1,  Xiao-Long Wang 1
Affiliations

Affiliations

  • 1 National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2 R&D Institute, Chia Tai Tianqing Pharmaceutical Group Co., LTD, Nanjing 211122, China.
  • 3 R&D Center, Gear Pharma, Nanjing 210000, China.
  • 4 The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 5 Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing 211198, China.
PMID: 39546350 DOI: 10.1021/acs.jmedchem.4c01727
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.

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