5HCV

Identification of Spirooxindole and Dibenzoxazepine Motifs as Potent Mineralocorticoid Receptor Antagonists

Summary for 5HCV

• Entry DOI: 10.2210/pdb5hcv/pdb
• Descriptor: Mineralocorticoid receptor, 6-[(~{E})-(3-fluoranyl-6~{H}-benzo[c][1]benzoxepin-11-ylidene)methyl]-4~{H}-1,4-benzoxazin-3-one, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: mineralocorticoid receptor, ligand-binding domain, mr-lbd, antagonists, co-crystal, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P08235
• Total number of polymer chains: 3
• Total formula weight: 90776.36

Authors

Chen, G.,McKeever, B.M. (deposition date: 2016-01-04, release date: 2016-03-09, Last modification date: 2024-11-13)

Primary citation

Lotesta, S.D.,Marcus, A.P.,Zheng, Y.,Leftheris, K.,Noto, P.B.,Meng, S.,Kandpal, G.,Chen, G.,Zhou, J.,McKeever, B.,Bukhtiyarov, Y.,Zhao, Y.,Lala, D.S.,Singh, S.B.,McGeehan, G.M.
Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists.
Bioorg.Med.Chem., 24:1384-1391, 2016

PubMed Abstract: Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.

PubMed: 26897089
DOI: 10.1016/j.bmc.2016.02.014

Experimental method

X-RAY DIFFRACTION (2.5 Å)