6IAR

Tricyclic indazoles a novel class of selective estrogen receptor degrader antagonists

6IAR の概要

• エントリーDOI: 10.2210/pdb6iar/pdb
• 分子名称: Estrogen receptor, 3-[4-[(6~{R})-7-(2-methylpropyl)-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]phenyl]propanoic acid (3 entities in total)
• 機能のキーワード: nuclear hormone receptor inhibitor downregulation estrogen receptor modulators, dna binding protein
• 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: 27470.29

構造登録者

Scott, J.S.,Bailey, A.,Buttar, D.,Carbajo, R.J.,Curwen, J.,Davies, R.D.M.,Degorce, S.L.,Donald, C.,Gangl, E.,Greenwood, R.,Groombridge, S.D.,Johnson, T.,Lamont, S.,Lawson, M.,Lister, A.,Morrow, C.,Moss, T.,Pink, J.H.,Polanski, R. (登録日: 2018-11-27, 公開日: 2019-01-23, 最終更新日: 2024-05-15)

主引用文献

Scott, J.S.,Bailey, A.,Buttar, D.,Carbajo, R.J.,Curwen, J.,Davey, P.R.J.,Davies, R.D.M.,Degorce, S.L.,Donald, C.,Gangl, E.,Greenwood, R.,Groombridge, S.D.,Johnson, T.,Lamont, S.,Lawson, M.,Lister, A.,Morrow, C.J.,Moss, T.A.,Pink, J.H.,Polanski, R.
Tricyclic Indazoles-A Novel Class of Selective Estrogen Receptor Degrader Antagonists.
J.Med.Chem., 62:1593-1608, 2019

PubMed Abstract: Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.

PubMed: 30640465
DOI: 10.1021/acs.jmedchem.8b01837

実験手法

X-RAY DIFFRACTION (1.84 Å)