Discovery of N-(2-benzyl-4-oxochroman-7-yl)-2-(5-(ethylsulfonyl) pyridin-2-yl) acetamide (b12) as a potent, selective, and orally available novel retinoic acid receptor-related orphan receptor γt inverse agonist.

Autor: Chen L; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China., Su M; Jiangsu Carefree Pharmaceutical Co., Ltd, Nanjing 210042, China., Jin Q; Jiangsu Carefree Pharmaceutical Co., Ltd, Nanjing 210042, China., Wang CG; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China., Assani I; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China., Wang MX; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China., Zhao SF; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China., Lv SM; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China., Wang JW; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China., Sun B; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China., Li Y; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China., Liao ZX; Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering and Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China. Electronic address: zxliao@seu.edu.cn.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2022 Feb; Vol. 119, pp. 105483. Date of Electronic Publication: 2021 Nov 17.
DOI: 10.1016/j.bioorg.2021.105483
Abstrakt: The nuclear receptor retinoic acid receptor-related orphan receptor γ (RORγ, NR1F3, or RORc) exists in two isoforms, with one isoform (RORγ or RORc1) widely expressed in a variety of tissues, and the expression of the second isoform (RORγt or RORc2) restricted to the thymus and cells of the immune system. RORγt is a key regulator of the development and functions of T-helper 17 (Th17) cells. Clinical proof-of-concept (PoC) with small molecule inverse agonists of RORγt has been achieved with VTP-43742 (Phase II) for the treatment of psoriasis, and pre-clinical PoC for this mechanism has also been established for the treatment of autoimmune diseases. A series of aryl sulfonyl derivatives as novel RORγt inverse agonists were designed and synthesized based on VTP-43742. We conducted structural modifications that improved the activity profile. In pharmacodynamic (PD) studies, oral administration of compound b12 showed robust and dose-dependent inhibition of IL-6 and IL-17A cytokine expression. The ability of compound b12 to reduce the levels of IL-6 and IL-17A in vivo after oral dosing in mice, and a corresponding reduction in skin inflammation further supports the potential of small molecule RORγt modulation as a therapeutic target for the treatment of inflammatory diseases.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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