| 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 PubMed
A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORgammat) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORgammat in a mouse PD (pharmacodynamic) model upon oral administration.
Discovery of orally efficacious RORgammat inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds.,Shirai J, Tomata Y, Kono M, Ochida A, Fukase Y, Sato A, Masada S, Kawamoto T, Yonemori K, Koyama R, Nakagawa H, Nakayama M, Uga K, Shibata A, Koga K, Okui T, Shirasaki M, Skene R, Sang B, Hoffman I, Lane W, Fujitani Y, Yamasaki M, Yamamoto S Bioorg Med Chem. 2017 Dec 9. pii: S0968-0896(17)31989-2. doi:, 10.1016/j.bmc.2017.12.006. PMID:29262987[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shirai J, Tomata Y, Kono M, Ochida A, Fukase Y, Sato A, Masada S, Kawamoto T, Yonemori K, Koyama R, Nakagawa H, Nakayama M, Uga K, Shibata A, Koga K, Okui T, Shirasaki M, Skene R, Sang B, Hoffman I, Lane W, Fujitani Y, Yamasaki M, Yamamoto S. Discovery of orally efficacious RORgammat inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds. Bioorg Med Chem. 2017 Dec 9. pii: S0968-0896(17)31989-2. doi:, 10.1016/j.bmc.2017.12.006. PMID:29262987 doi:http://dx.doi.org/10.1016/j.bmc.2017.12.006
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