Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: structure-activity relationship of the aryl region.
The structure-activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1.
Probst
Gary D
GD
Department of Medicinal Chemistry, Elan Pharmaceuticals, South San Francisco, CA 94080, USA.
Bowers
Simeon
S
Sealy
Jennifer M
JM
Stupi
Brian
B
Dressen
Darren
D
Jagodzinska
Barbara M
BM
Aquino
Jose
J
Gailunas
Andrea
A
Truong
Anh P
AP
Tso
Luke
L
Xu
Ying-Zi
YZ
Hom
Roy K
RK
John
Varghese
V
Tung
Jay S
JS
Pleiss
Michael A
MA
Tucker
John A
JA
Konradi
Andrei W
AW
Sham
Hing L
HL
Jagodzinski
Jacek
J
Toth
Gergely
G
Brecht
Eric
E
Yao
Nanhua
N
Pan
Hu
H
Lin
May
M
Artis
Dean R
DR
Ruslim
Lany
L
Bova
Michael P
MP
Sinha
Sukanto
S
Yednock
Ted A
TA
Gauby
Shawn
S
Zmolek
Wes
W
Quinn
Kevin P
KP
Sauer
John-Michael
JM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005021:Ethylamines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human