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Identification of novel quinazolinedione derivatives as RORγt inverse agonist.

Fukase Y, Sato A, Tomata Y, Ochida A, Kono M, Yonemori K, Koga K, Okui T, Yamasaki M, Fujitani Y, Nakagawa H, Koyama R, Nakayama M, Skene R, Sang BC, Hoffman I, Shirai J, Yamamoto S
Bioorg Med Chem 26 721-736 (2018)
Cited: 9 times
EuropePMC logo PMID: 29342416

Abstract

Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed.

Reviews citing this publication (3)

  1. (Inverse) Agonists of Retinoic Acid-Related Orphan Receptor γ: Regulation of Immune Responses, Inflammation, and Autoimmune Disease. Jetten AM, Cook DN. Annu Rev Pharmacol Toxicol 60 371-390 (2020)
  2. Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies. Gao Y, Zhou J, Li J. Cancer Sci 112 962-969 (2021)
  3. Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases. Zeng J, Li M, Zhao Q, Chen M, Zhao L, Wei S, Yang H, Zhao Y, Wang A, Shen J, Du F, Chen Y, Deng S, Wang F, Zhang Z, Li Z, Wang T, Wang S, Xiao Z, Wu X. J Pharm Anal 13 545-562 (2023)

Articles citing this publication (6)



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