4PF3

Mineralocorticoid receptor ligand-binding domain with compuond 37a

Summary for 4PF3

• Entry DOI: 10.2210/pdb4pf3/pdb
• Descriptor: 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)
• Functional Keywords: nuclear receptor, transcription factor, hypertension, non-steroidal antagonist, activating mutation, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32578.57

Authors

Sogabe, S.,Habuka, N. (deposition date: 2014-04-28, release date: 2014-11-26, Last modification date: 2023-11-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.1 Å)