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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

A SAR Study on a Class of 6-(Trifluoromethyl)-pyridine Derivatives as RORγt Inverse Agonists

Author(s): Yi-Yuan Ma, Yu-Hao Cao, Li-Jin Yang, Shi-Han Wu, Zhen-Jiang Tong, Jia-Zhen Wu, Yi-Bo Wang, Jiu-Kai Sha, Chen-Qian Zhang, Xin-Rui Zheng, Jiao Cai, Zi-Jun Chen, Qing-Xin Wang, Jing-Jing Wang, Jing-Han Zhao, Liang Chang, Ning Ding, Xue-Jiao Leng, Jin-Guo Xu, Wei-Chen Dai, Shan-Liang Sun, Yan-Cheng Yu*, Xiao-Long Wang*, Nian-Guang Li* and Xin Xue*

Volume 21, Issue 12, 2024

Published on: 26 September, 2023

Page: [2359 - 2373] Pages: 15

DOI: 10.2174/0115701808234886230921063622

Price: $65

Abstract

Background: The nuclear retinoic acid-related orphan receptor γt (RORγt) is an important transcription factor in immune cells. Functionally, RORγt plays an important role in promoting the differentiation of T helper 17 cells and regulating the expression of proinflammatory factors, such as interleukin 17. Therefore, RORγt is considered a promising target for the treatment of the autoimmune disorder. Currently, 21 RORγt inverse agonists with various scaffolds have entered clinical trials.

Objective: To discover novel and potent RORγt inverse agonists, a series of novel 6-(trifluoromethyl) pyridine derivatives were designed and synthesized.

Methods: We designed and synthesized a series of potent RORγt inverse agonists W1~W16 based on VTP-43742. Molecular docking, molecular dynamics (MD) simulation, and MM/GBSA were used to study the structure-activity relationship (SAR) of the derivatives.

Results: The biological activity evaluation indicated that the target compounds showed potent RORγt inhibitory activity. The most active compound, W14, exhibited low nanomolar inhibitory activity (IC50 = 7.5 nM) in the luciferase reporter assay, which was superior to the clinical compound VTP-43742. Analysis of the binding mode of W14 demonstrated that the interaction of -CF3 with Leu324, Leu396, and His479 has an important contribution to the binding. Furthermore, W14 broke the H-bond formed by His479 and Tyr502 via a “push-pull” mechanism.

Conclusion: Compound W14 could be used as a potential RORγt inverse agonist for further modification.

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