Title
|
|
|
|
2-amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (-site APP cleaving enzyme) : use of structure based design to convert a micromolar hit into a nanomolar lead
|
|
Author
|
|
|
|
|
|
Abstract
|
|
|
|
A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 mu M to 11 nM K-i) by substitution into the unoccupied S-1 ' pocket. |
|
|
Language
|
|
|
|
English
|
|
Source (journal)
|
|
|
|
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
|
|
Publication
|
|
|
|
Washington, D.C.
:
2007
|
|
ISSN
|
|
|
|
0022-2623
[print]
1520-4804
[online]
|
|
DOI
|
|
|
|
10.1021/JM0705408
|
|
Volume/pages
|
|
|
|
50
:18
(2007)
, p. 4261-4264
|
|
ISI
|
|
|
|
000249150700001
|
|
Full text (Publisher's DOI)
|
|
|
|
|
|