6b31
From Proteopedia
Structure of RORgt in complex with a novel inverse agonist 2
Structural highlights
Function[RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. Publication Abstract from PubMedNovel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORgammat) 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 RORgammat inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORgammat protein was also observed. Identification of novel quinazolinedione derivatives as RORgammat 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. 2018 Feb 1;26(3):721-736. doi: 10.1016/j.bmc.2017.12.039. Epub, 2017 Dec 28. PMID:29342416[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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