6IVX

Discovery of the Second Generation ROR gamma Inhibitors Composed of an Azole Scaffold.

6IVX の概要

• エントリーDOI: 10.2210/pdb6ivx/pdb
• 分子名称: Nuclear receptor ROR-gamma, Nuclear receptor corepressor 2, (4S)-4-[4'-cyclopropyl-5-(2,2-dimethylpropyl)[3,5'-bi-1,2-oxazol]-3'-yl]-6-[(2,4-dichlorophenyl)amino]-6-oxohexanoic acid, ... (4 entities in total)
• 機能のキーワード: ternary complex, nuclear receptor, nuclear protein, nuclear protein-inhibitor complex, immune system, nuclear protein/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 131554.93

構造登録者

Noguchi, M.,Nomura, A.,Doi, S.,Adachi, T. (登録日: 2018-12-04, 公開日: 2019-03-06, 最終更新日: 2023-11-22)

主引用文献

Kotoku, M.,Maeba, T.,Fujioka, S.,Yokota, M.,Seki, N.,Ito, K.,Suwa, Y.,Ikenogami, T.,Hirata, K.,Hase, Y.,Katsuda, Y.,Miyagawa, N.,Arita, K.,Asahina, K.,Noguchi, M.,Nomura, A.,Doi, S.,Adachi, T.,Crowe, P.,Tao, H.,Thacher, S.,Hashimoto, H.,Suzuki, T.,Shiozaki, M.
Discovery of Second Generation ROR gamma Inhibitors Composed of an Azole Scaffold.
J. Med. Chem., 62:2837-2842, 2019

PubMed Abstract: Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.

PubMed: 30776227
DOI: 10.1021/acs.jmedchem.8b01567

実験手法

X-RAY DIFFRACTION (2.35 Å)