In:
Letters in Drug Design & Discovery, Bentham Science Publishers Ltd., Vol. 20 ( 2023-09-26)
Kurzfassung:
To discover novel and potent RORγt inverse agonists for the treatment of Th17 cell-related autoimmune diseases such as psoriasis, and rheumatoid arthritis. background: The nuclear receptor retinoic acid receptor-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 pro-inflammatory 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. method: 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. result: The biological activity evaluation indicated that the target compounds showed potent RORγt inhibitory activities. 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. other: No
Materialart:
Online-Ressource
ISSN:
1570-1808
DOI:
10.2174/0115701808234886230921063622
Sprache:
Englisch
Verlag:
Bentham Science Publishers Ltd.
Publikationsdatum:
2023
SSG:
15,3
