PDBsum entry 4pf3

Transcription/transcription inhibitor

PDB id: 4pf3

Contents

Protein chain

249 a.a.

Ligands

HFN

EDO ×8

Waters ×224

PDB id:

4pf3

Name:

Transcription/transcription inhibitor

Title:

Mineralocorticoid receptor ligand-binding domain with compuond 37a

Structure:

Mineralocorticoid receptor. Chain: a. Fragment: unp residues 716-988. Synonym: mr,nuclear receptor subfamily 3 group c member 2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: nr3c2, mcr, mlr. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.10Å R-factor: 0.155 R-free: 0.177

Authors:

S.Sogabe,N.Habuka

Key ref:

T.Hasui et al. (2014). 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 Lett, 22, 5428-5445. PubMed id: 25187277 DOI: 10.1016/j.bmc.2014.07.038

Date:

28-Apr-14 Release date: 26-Nov-14

Protein chain

P08235  (MCR_HUMAN) -  Mineralocorticoid receptor from Homo sapiens

Seq: 984 a.a.

Struc: 249 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

DOI no: 10.1016/j.bmc.2014.07.038

Bioorg Med Chem Lett 22:5428-5445 (2014)

PubMed id: 25187277

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists.

T.Hasui, N.Ohyabu, T.Ohra, K.Fuji, T.Sugimoto, J.Fujimoto, K.Asano, M.Oosawa, S.Shiotani, N.Nishigaki, K.Kusumoto, H.Matsui, A.Mizukami, N.Habuka, S.Sogabe, S.Endo, M.Ono, C.S.Siedem, T.P.Tang, C.Gauthier, L.A.De Meese, S.A.Boyd, S.Fukumoto.

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.