6IVX

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

Summary for 6IVX

• Entry DOI: 10.2210/pdb6ivx/pdb
• Descriptor: 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)
• Functional Keywords: ternary complex, nuclear receptor, nuclear protein, nuclear protein-inhibitor complex, immune system, nuclear protein/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 131554.93

Authors

Noguchi, M.,Nomura, A.,Doi, S.,Adachi, T. (deposition date: 2018-12-04, release date: 2019-03-06, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.35 Å)