7LUK

CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS-RORGT(244-487)-L6-SRC1(678-692) IN COMPLEX WITH AN AZATRICYCLIC RORGT INVERSE AGONIST

7LUK の概要

• エントリーDOI: 10.2210/pdb7luk/pdb
• 分子名称: Nuclear receptor ROR-gamma, (2S)-N-[(6aS,7R,9aS)-9a-[(4-fluorophenyl)sulfonyl]-3-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6,6a,7,8,9,9a-hexahydro-5H-cyclopenta[f]quinolin-7-yl]-2-hydroxy-2-methyl-3-(methylsulfonyl)propanamide (3 entities in total)
• 機能のキーワード: rorgt, nuclear hormone receptor, ligand-binding domain, inverse agonist, ransferase-transferase inhibitor complex, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33565.53

構造登録者

Sack, J.S. (登録日: 2021-02-22, 公開日: 2021-05-12, 最終更新日: 2023-10-18)

主引用文献

Liu, Q.,Xiao, H.Y.,Batt, D.G.,Xiao, Z.,Zhu, Y.,Yang, M.G.,Li, N.,Yip, S.,Li, P.,Sun, D.,Wu, D.R.,Ruzanov, M.,Sack, J.S.,Weigelt, C.A.,Wang, J.,Li, S.,Shuster, D.J.,Xie, J.H.,Song, Y.,Sherry, T.,Obermeier, M.T.,Fura, A.,Stefanski, K.,Cornelius, G.,Chacko, S.,Khandelwal, P.,Dudhgaonkar, S.,Rudra, A.,Nagar, J.,Murali, V.,Govindarajan, A.,Denton, R.,Zhao, Q.,Meanwell, N.A.,Borzilleri, R.,Dhar, T.G.M.
Azatricyclic Inverse Agonists of ROR gamma t That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis.
Acs Med.Chem.Lett., 12:827-835, 2021

PubMed Abstract: Structure-activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by with heterocyclic moieties led to the identification of three novel aza analogs -. The hexahydropyrrolo[3,2-]quinoline series (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series but with improved membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series , culminating in the discovery of as a potent and selective RORγt inverse agonist with an excellent profile, good pharmacokinetic properties, and biologic-like efficacy in preclinical models of rheumatoid arthritis and psoriasis.

PubMed: 34055233
DOI: 10.1021/acsmedchemlett.1c00112

実験手法

X-RAY DIFFRACTION (2.087 Å)