6XZ9

Structure of aldosterone synthase (CYP11B2) in complex with 5-chloro-3,3-dimethyl-2-[5-[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxy-3-pyridyl]isoindolin-1-one

6XZ9 の概要

• エントリーDOI: 10.2210/pdb6xz9/pdb
• 関連するPDBエントリー: 6XZ8
• 分子名称: Cytochrome P450 11B2, mitochondrial, HEME C, 5-chloranyl-3,3-dimethyl-2-[5-[1-(1-methylpyrazol-4-yl)carbonylazetidin-3-yl]oxypyridin-3-yl]isoindol-1-one, ... (4 entities in total)
• 機能のキーワード: cytochrome p450, cyp11b2, aldosterone synthase, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 171937.82

構造登録者

Kuglstatter, A.,Joseph, C.,Benz, J. (登録日: 2020-02-03, 公開日: 2020-06-24, 最終更新日: 2024-05-01)

主引用文献

Liu, Y.,Wu, J.,Zhou, M.,Chen, W.,Li, D.,Wang, Z.,Hornsperger, B.,Aebi, J.D.,Marki, H.P.,Kuhn, B.,Wang, L.,Kuglstatter, A.,Benz, J.,Muller, S.,Hochstrasser, R.,Ottaviani, G.,Xin, J.,Kirchner, S.,Mohr, S.,Verry, P.,Riboulet, W.,Shen, H.C.,Mayweg, A.V.,Amrein, K.,Tan, X.
Discovery of 3-Pyridyl Isoindolin-1-one Derivatives as Potent, Selective, and Orally Active Aldosterone Synthase (CYP11B2) Inhibitors.
J.Med.Chem., 63:6876-6897, 2020

PubMed Abstract: Aldosterone synthase (CYP11B2) inhibitors have been explored in recent years as an alternative therapeutic option to mineralocorticoid receptor (MR) antagonists to reduce elevated aldosterone levels, which are associated with deleterious effects on various organ systems including the heart, vasculature, kidney, and central nervous system (CNS). A benzamide pyridine hit derived from a focused screen was successfully developed into a series of potent and selective 3-pyridyl isoindolin-1-ones CYP11B2 inhibitors. Our systematic structure-activity relationship study enabled us to identify unique structural features that result in high selectivity against the closely homologous cortisol synthase (CYP11B1). We evaluated advanced lead molecules, exemplified by compound , in an cynomolgus monkey acute adrenocorticotropic hormone (ACTH) challenge model and demonstrated a superior 100-fold selectivity against CYP11B1.

PubMed: 32530624
DOI: 10.1021/acs.jmedchem.0c00233

実験手法

X-RAY DIFFRACTION (2.77 Å)