7JTW

Crystal structure of RORgt with compound (4R)-6-[(2,5-dichloro-3-{[(2R,4R)-1-(cyclopentanecarbonyl)-2-methylpiperidin-4-yl]oxy}phenyl)amino]-6-oxo-4-phenylhexanoic acid

Summary for 7JTW

• Entry DOI: 10.2210/pdb7jtw/pdb
• Descriptor: RAR-related orphan receptor C isoform a variant, (4R)-6-[(2,5-dichloro-3-{[(2R,4R)-1-(cyclopentanecarbonyl)-2-methylpiperidin-4-yl]oxy}phenyl)amino]-6-oxo-4-phenylhexanoic acid, GLYCEROL, ... (5 entities in total)
• Functional Keywords: nuclear receptor, nuclear protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32149.89

Authors

Min, X.,Wang, Z. (deposition date: 2020-08-18, release date: 2021-02-03, Last modification date: 2023-10-18)

Primary citation

Nakajima, R.,Oono, H.,Kumazawa, K.,Ida, T.,Hirata, J.,White, R.D.,Min, X.,Guzman-Perez, A.,Wang, Z.,Symons, A.,Singh, S.K.,Mothe, S.R.,Belyakov, S.,Chakrabarti, A.,Shuto, S.
Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as ROR gamma t inverse agonists showing favorable ADME profile.
Bioorg.Med.Chem.Lett., 36:127786-127786, 2021

PubMed Abstract: The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile.

PubMed: 33493627
DOI: 10.1016/j.bmcl.2021.127786

Experimental method

X-RAY DIFFRACTION (1.9 Å)