Discovery of isonicotinamide derived beta-secretase inhibitors: in vivo reduction of beta-amyloid.
beta-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate beta-amyloid lowering in a murine model.
Stanton
Matthew G
MG
Stauffer
Shaun R
SR
Gregro
Alison R
AR
Steinbeiser
Melissa
M
Nantermet
Philippe
P
Sankaranarayanan
Sethu
S
Price
Eric A
EA
Wu
Guoxin
G
Crouthamel
Ming-Chih
MC
Ellis
Joan
J
Lai
Ming-Tain
MT
Espeseth
Amy S
AS
Shi
Xiao-Ping
XP
Jin
Lixia
L
Colussi
Dennis
D
Pietrak
Beth
B
Huang
Qian
Q
Xu
Min
M
Simon
Adam J
AJ
Graham
Samuel L
SL
Vacca
Joseph P
JP
Selnick
Harold
H
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007539:Isonicotinic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D016229:Amyloid beta-Peptides; D007539:Isonicotinic Acids; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases