 |
PDBsum entry 4xkx
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
4xkx
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Hydrolase/hydrolase inhibitor
|
|
|
Title:
|
|
Crystal structure of bace1 in complex with 2-aminooxazoline 3- azaxanthene inhibitor 28
|
|
Structure:
|
|
Beta-secretase 1. Chain: a. Fragment: unp residues 43-453. Synonym: aspartyl protease 2,asp 2,beta-site amyloid precursor protein cleaving enzyme 1,beta-site app cleaving enzyme 1,memapsin-2, membrane-associated aspartic protease 2. Engineered: yes. Mutation: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: bace1, bace, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 562
|
|
Resolution:
|
|
|
1.80Å
|
R-factor:
|
0.194
|
R-free:
|
0.228
|
|
|
Authors:
|
|
D.A.Whittington,A.M.Long
|
|
Key ref:
|
|
J.J.Chen
et al.
(2015).
Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease.
Bioorg Med Chem Lett,
25,
767-774.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
12-Jan-15
|
Release date:
|
04-Feb-15
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P56817
(BACE1_HUMAN) -
Beta-secretase 1 from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
501 a.a.
363 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
Bioorg Med Chem Lett
25:767-774
(2015)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease.
|
|
J.J.Chen,
Q.Liu,
C.Yuan,
V.Gore,
P.Lopez,
V.Ma,
A.Amegadzie,
W.Qian,
T.C.Judd,
A.E.Minatti,
J.Brown,
Y.Cheng,
M.Xue,
W.Zhong,
T.A.Dineen,
O.Epstein,
J.Human,
C.Kreiman,
I.Marx,
M.M.Weiss,
S.A.Hitchcock,
T.S.Powers,
K.Chen,
P.H.Wen,
D.A.Whittington,
A.C.Cheng,
M.D.Bartberger,
D.Hickman,
J.A.Werner,
H.M.Vargas,
N.E.Everds,
S.L.Vonderfecht,
R.T.Dunn,
S.Wood,
R.T.Fremeau,
R.D.White,
V.F.Patel.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of
the most hotly pursued targets for the treatment of Alzheimer's disease. We used
a structure- and property-based drug design approach to identify
2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly
reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the
initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in
a non-human primate cardiovascular safety model.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
