1. Discovery of 2H-chromone-4-one based sulfonamide derivatives as potent retinoic acid receptor-related orphan receptor γt inverse agonists.
- Author
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Chen L, Su M, Wu XZ, Wang DZ, Kang YY, Wang CG, Assani I, Wang MX, Zhao SF, Lv SM, Wang JW, Sun B, Li Y, Jin Q, Huang RZ, and Liao ZX
- Subjects
- Amino Acid Sequence, Animals, Disease Models, Animal, Drug Development, Drug Inverse Agonism, Female, Humans, Imiquimod metabolism, Interleukin-17 metabolism, Molecular Docking Simulation, Protein Binding, Protein Conformation, Pyrans pharmacology, Pyrans standards, Skin, Structure-Activity Relationship, Sulfonamides administration & dosage, Sulfonamides adverse effects, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Sulfonamides standards, Th17 Cells, Autoimmune Diseases drug therapy, Chromones chemistry, Inflammation drug therapy, Receptors, Retinoic Acid agonists, Sulfonamides chemical synthesis
- Abstract
Retinoic acid receptor related orphan receptor γt (RORγt), identified as the essential functional regulator of IL-17 producing Th17 cells, is an attractive drug target for treating autoimmune diseases. Starting from the reported GSK2981278 (Phase II), we structurally modified and synthesized a series of 2H-chromone-4-one based sulfonamide derivatives as novel RORγt inverse agonists, which significantly improved their human metabolic stabilities while maintaining a potent RORγt inverse agonist profile. Efforts in reducing the lipophilicity and improving the LLE values led to the discovery of c9, which demonstrated potent RORγt inverse agonistic activity and consistent metabolic stability. During in vivo studies, oral administration of compound c9 exhibited a robust and dose-dependent inhibition of IL-17A cytokine expression and significantly lessened the skin inflammatory symptoms in the mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that c9 can suitably occupy the active pocket, and the introduction of the morpholine pyridine group can interact with Leu396, His479, and Cys393. Thus, compound c9 was selected as a preclinical compound for treating Th17-driven autoimmune diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Published
- 2022
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