2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead.
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 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.
Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, Pennsylvania 19477, USA. ebaxter@prdus.jnj.com
Ellen W
EW
Baxter
Kelly A
KA
Conway
Ludo
L
Kennis
François
F
Bischoff
Marc H
MH
Mercken
Hans L De
HL
Winter
Charles H
CH
Reynolds
Brett A
BA
Tounge
Chi
C
Luo
Malcolm K
MK
Scott
Yifang
Y
Huang
Mirielle
M
Braeken
Serge M A
SM
Pieters
Didier J C
DJ
Berthelot
Stefan
S
Masure
Wouter D
WD
Bruinzeel
Alfonzo D
AD
Jordan
Michael H
MH
Parker
Robert E
RE
Boyd
Junya
J
Qu
Richard S
RS
Alexander
Douglas E
DE
Brenneman
Allen B
AB
Reitz
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016466:CHO Cells; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C414614:OM99-2; D009842:Oligopeptides; D010446:Peptide Fragments; D011799:Quinazolines; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human