Title
2-amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (<tex>$\beta$</tex>-site APP cleaving enzyme) : use of structure based design to convert a micromolar hit into a nanomolar lead 2-amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (<tex>$\beta$</tex>-site APP cleaving enzyme) : use of structure based design to convert a micromolar hit into a nanomolar lead
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
Washington, D.C. ,
Subject
Pharmacology. Therapy
Source (journal)
Journal of medicinal chemistry. - Washington, D.C., 1963, currens
Volume/pages
50(2007) :18 , p. 4261-4264
ISSN
0022-2623
0022-2623
ISI
000249150700001
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
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.
E-info
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