Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model.
In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.
Truong
Anh P
AP
Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, United States.
Tóth
Gergley
G
Probst
Gary D
GD
Sealy
Jennifer M
JM
Bowers
Simeon
S
Wone
David W G
DW
Dressen
Darren
D
Hom
Roy K
RK
Konradi
Andrei W
AW
Sham
Hing L
HL
Wu
Jing
J
Peterson
Brian T
BT
Ruslim
Lany
L
Bova
Michael P
MP
Kholodenko
Dora
D
Motter
Ruth N
RN
Bard
Frédérique
F
Santiago
Pamela
P
Ni
Huifang
H
Chian
David
D
Soriano
Ferdie
F
Cole
Tracy
T
Brigham
Elizabeth F
EF
Wong
Karina
K
Zmolek
Wes
W
Goldbach
Erich
E
Samant
Bhushan
B
Chen
Linda
L
Zhang
Hongbing
H
Nakamura
David F
DF
Quinn
Kevin P
KP
Yednock
Ted A
TA
Sauer
John-Michael
JM
D000478:Alkylation; D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D005021:Ethylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D007202:Indicators and Reagents; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D005021:Ethylamines; D007202:Indicators and Reagents; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human