7JH2

CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C IN COMPLEX WITH A POTENT, SELECTIVE AND ORALLY BIOAVAILABLE ROR-GAMMA-T INVERSE AGONIST

7JH2 の概要

• エントリーDOI: 10.2210/pdb7jh2/pdb
• 分子名称: Nuclear receptor ROR-gamma, 2-({[2-(4-{(3R)-1-(4-acetylpiperazine-1-carbonyl)-3-[(4-fluorophenyl)sulfonyl]pyrrolidin-3-yl}phenyl)-1,1,1,3,3,3-hexafluoropropan-2-yl]oxy}methyl)-3-fluorobenzonitrile, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: rorgt, nuclear hormone receptor, ligand-binding domain, inverse agonist, transcription-agonist complex, transcription/agonist
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63132.39

構造登録者

Sack, J.S. (登録日: 2020-07-20, 公開日: 2020-08-12, 最終更新日: 2023-10-18)

主引用文献

Duan, J.J.,Jiang, B.,Lu, Z.,Stachura, S.,Weigelt, C.A.,Sack, J.S.,Khan, J.,Ruzanov, M.,Wu, D.R.,Yarde, M.,Shen, D.R.,Zhao, Q.,Salter-Cid, L.M.,Carter, P.H.,Murali Dhar, T.G.
Discovery of 2,6-difluorobenzyl ether series of phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfones as surprisingly potent, selective and orally bioavailable ROR gamma t inverse agonists.
Bioorg.Med.Chem.Lett., 30:127441-127441, 2020

PubMed Abstract: In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC 11 nM) that are highly selective against PXR, LXRα and LXRβ. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.

PubMed: 32736080
DOI: 10.1016/j.bmcl.2020.127441

実験手法

X-RAY DIFFRACTION (2.367 Å)