6GEV

Mineralocorticoid receptor in complex with (s)-13

6GEV の概要

• エントリーDOI: 10.2210/pdb6gev/pdb
• 分子名称: Mineralocorticoid receptor, Nuclear receptor coactivator 1, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: mineralocorticoid receptor, nuclear hormone receptor, steroid receptor, ligand complex, peptide complex, signaling protein, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37219.39

構造登録者

Edman, K.,Aagaard, A.,Tangefjord, S. (登録日: 2018-04-27, 公開日: 2019-01-09, 最終更新日: 2024-05-15)

主引用文献

Granberg, K.L.,Yuan, Z.Q.,Lindmark, B.,Edman, K.,Kajanus, J.,Hogner, A.,Malmgren, M.,O'Mahony, G.,Nordqvist, A.,Lindberg, J.,Tangefjord, S.,Kossenjans, M.,Lofberg, C.,Branalt, J.,Liu, D.,Selmi, N.,Nikitidis, G.,Nordberg, P.,Hayen, A.,Aagaard, A.,Hansson, E.,Hermansson, M.,Ivarsson, I.,Jansson-Lofmark, R.,Karlsson, U.,Johansson, U.,William-Olsson, L.,Hartleib-Geschwindner, J.,Bamberg, K.
Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection.
J.Med.Chem., 62:1385-1406, 2019

PubMed Abstract: The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators ( S)-1 and ( S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na/K ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of ( S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases, including chronic kidney disease and heart failure. On the basis of our findings, we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na/K ratio in vivo.

PubMed: 30596500
DOI: 10.1021/acs.jmedchem.8b01523

実験手法

X-RAY DIFFRACTION (1.54 Å)