6B30

Structure of RORgt in complex with a novel inverse agonist 1

Summary for 6B30

• Entry DOI: 10.2210/pdb6b30/pdb
• Descriptor: Nuclear receptor ROR-gamma, N-[(1R)-1-(4-methoxyphenyl)-2-oxo-2-{[4-(trimethylsilyl)phenyl]amino}ethyl]-N-methyl-3-oxo-2,3-dihydro-1,2-oxazole-5-carboxamide (3 entities in total)
• Functional Keywords: complex, inverse agonist, nuclear hormone receptor, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P51449
• Total number of polymer chains: 2
• Total formula weight: 50908.96

Authors

Skene, R.J.,Hoffman, I. (deposition date: 2017-09-20, release date: 2018-01-03, Last modification date: 2024-03-13)

Primary citation

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 ROR gamma t inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds.
Bioorg. Med. Chem., 26:483-500, 2018

PubMed Abstract: A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) 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 RORγt in a mouse PD (pharmacodynamic) model upon oral administration.

PubMed: 29262987
DOI: 10.1016/j.bmc.2017.12.006

Experimental method

X-RAY DIFFRACTION (2.69 Å)