Modes of action insights from the crystallographic structures of retinoic acid receptor-related orphan receptor-γt (RORγt)

Zhang, Junjie; Chen, Baiyu; Zhang, Chao; Sun, Nannan; Huang, Xiaoqin; Wang, Wuqing; Fu, Wei

doi:10.1016/j.ejmech.2022.115039

European Journal of Medicinal Chemistry

2023

DOI: 10.1016/j.ejmech.2022.115039

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Modes of action insights from the crystallographic structures of retinoic acid receptor-related orphan receptor-γt (RORγt)

Junjie Zhang

Baiyu Chen

Chao Zhang

et al.

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2024

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

Sun,

Xu,

Jiang

et al. 2024

J. Med. Chem.

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

Sun,

Xu,

Jiang

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

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Modes of action insights from the crystallographic structures of retinoic acid receptor-related orphan receptor-γt (RORγt)

Cited by 1 publication

References 87 publications

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

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