4PF3

Mineralocorticoid receptor ligand-binding domain with compuond 37a

4PF3 の概要

• エントリーDOI: 10.2210/pdb4pf3/pdb
• 分子名称: Mineralocorticoid receptor, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: nuclear receptor, transcription factor, hypertension, non-steroidal antagonist, activating mutation, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• 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: 32578.57

構造登録者

Sogabe, S.,Habuka, N. (登録日: 2014-04-28, 公開日: 2014-11-26, 最終更新日: 2023-11-08)

主引用文献

Hasui, T.,Ohyabu, N.,Ohra, T.,Fuji, K.,Sugimoto, T.,Fujimoto, J.,Asano, K.,Oosawa, M.,Shiotani, S.,Nishigaki, N.,Kusumoto, K.,Matsui, H.,Mizukami, A.,Habuka, N.,Sogabe, S.,Endo, S.,Ono, M.,Siedem, C.S.,Tang, T.P.,Gauthier, C.,De Meese, L.A.,Boyd, S.A.,Fukumoto, S.
Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists
Bioorg.Med.Chem., 22:5428-5445, 2014

PubMed Abstract: In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.

PubMed: 25187277
DOI: 10.1016/j.bmc.2014.07.038

実験手法

X-RAY DIFFRACTION (1.1 Å)