 |
PDBsum entry 4x48
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Membrane protein
|
PDB id
|
|
|
|
4x48
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Membrane protein
|
|
|
Title:
|
|
Crystal structure of glur2 ligand-binding core
|
|
Structure:
|
|
Glutamate receptor 2. Chain: a, b, c. Fragment: ligand binding domain, engineered single chain. Synonym: glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2, glutamate receptor ionotropic,ampa 2,glua2,glur-2,ampa-selective glutamate receptor 2,glur-b,glur-k2,glutamate receptor ionotropic, ampa 2,glua2. Engineered: yes
|
|
Source:
|
|
Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: gria2, glur2. Expressed in: escherichia coli. Expression_system_taxid: 562
|
|
Resolution:
|
|
|
1.89Å
|
R-factor:
|
0.175
|
R-free:
|
0.197
|
|
|
Authors:
|
|
J.Pandit
|
|
Key ref:
|
|
C.L.Shaffer
et al.
(2015).
The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242).
J Med Chem,
58,
4291-4308.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
02-Dec-14
|
Release date:
|
06-May-15
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P19491
(GRIA2_RAT) -
Glutamate receptor 2 from Rattus norvegicus
|
|
|
|
Seq:
Struc:
|
|
|
|
883 a.a.
258 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
J Med Chem
58:4291-4308
(2015)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
The discovery and characterization of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiator N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242).
|
|
C.L.Shaffer,
N.C.Patel,
J.Schwarz,
R.J.Scialis,
Y.Wei,
X.J.Hou,
L.Xie,
K.Karki,
D.K.Bryce,
S.M.Osgood,
W.E.Hoffmann,
J.T.Lazzaro,
C.Chang,
D.F.McGinnis,
S.M.Lotarski,
J.Liu,
R.S.Obach,
M.L.Weber,
L.Chen,
K.R.Zasadny,
P.A.Seymour,
C.J.Schmidt,
M.Hajós,
R.S.Hurst,
J.Pandit,
C.J.O'Donnell.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
A unique tetrahydrofuran ether class of highly potent
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has
been identified using rational and structure-based drug design. An acyclic lead
compound, containing an ether-linked isopropylsulfonamide and biphenyl group,
was pharmacologically augmented by converting it to a conformationally
constrained tetrahydrofuran to improve key interactions with the human GluA2
ligand-binding domain. Subsequent replacement of the distal phenyl motif with
2-cyanothiophene to enhance its potency, selectivity, and metabolic stability
afforded
N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide
(PF-04958242, 3), whose preclinical characterization suggests an adequate
therapeutic index, aided by low projected human oral pharmacokinetic
variability, for clinical studies exploring its ability to attenuate cognitive
deficits in patients with schizophrenia.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
