Title:A SAR Study on a Class of 6-(Trifluoromethyl)-pyridine Derivatives as RORγt Inverse Agonists
Volume: 21
Issue: 12
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*, Xin Xue*Nian-Guang Li*
Affiliation:
- 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
- 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
- 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
- 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
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.
