6BR2

Structure of RORgt in complex with a novel isoquinoline inverse agonist.

Summary for 6BR2

• Entry DOI: 10.2210/pdb6br2/pdb
• Descriptor: Nuclear receptor ROR-gamma, (4S)-2-METHYL-2,4-PENTANEDIOL, (1R)-N-(4-tert-butyl-3-fluorophenyl)-6-methoxy-2-[(3-oxo-2,3-dihydro-1,2-oxazol-5-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline-1-carboxamide, ... (4 entities in total)
• Functional Keywords: nuclear hormone receptor, inverse agonist, complex, transcription-agonist complex, transcription/agonist
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P51449
• Total number of polymer chains: 2
• Total formula weight: 51201.21

Authors

Skene, R.J.,Hoffman, I. (deposition date: 2017-11-29, release date: 2018-03-21, Last modification date: 2024-03-13)

Primary citation

Kono, M.,Ochida, A.,Oda, T.,Imada, T.,Banno, Y.,Taya, N.,Masada, S.,Kawamoto, T.,Yonemori, K.,Nara, Y.,Fukase, Y.,Yukawa, T.,Tokuhara, H.,Skene, R.,Sang, B.C.,Hoffman, I.D.,Snell, G.P.,Uga, K.,Shibata, A.,Igaki, K.,Nakamura, Y.,Nakagawa, H.,Tsuchimori, N.,Yamasaki, M.,Shirai, J.,Yamamoto, S.
Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor gamma t Inverse Agonist.
J. Med. Chem., 61:2973-2988, 2018

PubMed Abstract: A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log  D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.

PubMed: 29510038
DOI: 10.1021/acs.jmedchem.8b00061

Experimental method

X-RAY DIFFRACTION (3.18 Å)