First demonstration of cerebrospinal fluid and plasma A beta lowering with oral administration of a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates.
beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A beta 42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A beta lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A beta in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC(50) approximately 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A beta levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A beta levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP beta, A beta 40, A beta 42, and plasma A beta 40 levels. CSF A beta 42 lowering showed an EC(50) of approximately 20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate.
Sankaranarayanan
Sethu
S
Department of Alzheimer's Research, WP 26A-2000, Merck Research Labs, 770 Sumneytown Pike, West Point, PA 19486, USA.
Holahan
Marie A
MA
Colussi
Dennis
D
Crouthamel
Ming-Chih
MC
Devanarayan
Viswanath
V
Ellis
Joan
J
Espeseth
Amy
A
Gates
Adam T
AT
Graham
Samuel L
SL
Gregro
Allison R
AR
Hazuda
Daria
D
Hochman
Jerome H
JH
Holloway
Katharine
K
Jin
Lixia
L
Kahana
Jason
J
Lai
Ming-tain
MT
Lineberger
Janet
J
McGaughey
Georgia
G
Moore
Keith P
KP
Nantermet
Philippe
P
Pietrak
Beth
B
Price
Eric A
EA
Rajapakse
Hemaka
H
Stauffer
Shaun
S
Steinbeiser
Melissa A
MA
Seabrook
Guy
G
Selnick
Harold G
HG
Shi
Xiao-Ping
XP
Stanton
Matthew G
MG
Swestock
John
J
Tugusheva
Katherine
K
Tyler
Keala X
KX
Vacca
Joseph P
JP
Wong
Jacky
J
Wu
Guoxin
G
Xu
Min
M
Cook
Jacquelynn J
JJ
Simon
Adam J
AJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D051379:Mice; D008822:Mice, Transgenic; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human