3VHU

Mineralocorticoid receptor ligand-binding domain with spironolactone

Summary for 3VHU

• Entry DOI: 10.2210/pdb3vhu/pdb
• Related: 2AB2 2OAX 3VHV
• Descriptor: Mineralocorticoid receptor, SPIRONOLACTONE (3 entities in total)
• Functional Keywords: nuclear receptor, transcription factor, activating mutation, hypertension, antagonist, spironolactone, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P08235
• Total number of polymer chains: 1
• Total formula weight: 34422.79

Authors

Sogabe, S.,Habuka, N. (deposition date: 2011-09-07, release date: 2011-12-28, Last modification date: 2023-11-08)

Primary citation

Hasui, T.,Matsunaga, N.,Ora, T.,Ohyabu, N.,Nishigaki, N.,Imura, Y.,Igata, Y.,Matsui, H.,Motoyaji, T.,Tanaka, T.,Habuka, N.,Sogabe, S.,Ono, M.,Siedem, C.S.,Tang, T.P.,Gauthier, C.,De Meese, L.A.,Boyd, S.A.,Fukumoto, S.
Identification of Benzoxazin-3-one Derivatives as Novel, Potent, and Selective Nonsteroidal Mineralocorticoid Receptor Antagonists
J.Med.Chem., 54:8616-8631, 2011

PubMed Abstract: Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H)-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.

PubMed: 22074142
DOI: 10.1021/jm2011645

Experimental method

X-RAY DIFFRACTION (2.11 Å)