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

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; Xin      Xue

doi:10.2174/0115701808234886230921063622

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.

Keywords: Th17 cells, RORγt, inverse agonist, SAR, MM/GBSA, molecular dynamic simulation.

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DOI https://dx.doi.org/10.2174/0115701808234886230921063622	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

Letters in Drug Design & Discovery

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

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