Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents.
Herein we describe further evolution of hydroxyethylamine inhibitors of BACE-1 with enhanced permeability characteristics necessary for CNS penetration. Variation at the P2' position of the inhibitor with more polar substituents led to compounds 19 and 32, which retained the potency of more lipophilic analog 1 but with much higher observed passive permeability in MDCK cellular assay.
Truong
Anh P
AP
Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States.
Probst
Gary D
GD
Aquino
Jose
J
Fang
Larry
L
Brogley
Louis
L
Sealy
Jennifer M
JM
Hom
Roy K
RK
Tucker
John A
JA
John
Varghese
V
Tung
Jay S
JS
Pleiss
Michael A
MA
Konradi
Andrei W
AW
Sham
Hing L
HL
Dappen
Michael S
MS
Tóth
Gergley
G
Yao
Nanhua
N
Brecht
Eric
E
Pan
Hu
H
Artis
Dean R
DR
Ruslim
Lany
L
Bova
Michael P
MP
Sinha
Sukanto
S
Yednock
Ted A
TA
Zmolek
Wes
W
Quinn
Kevin P
KP
Sauer
John-Michael
JM
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D000440:Butanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D003514:Cyclohexylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D000081:Acetamides; D000440:Butanols; D003514:Cyclohexylamines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human