Purine derivatives as potent gamma-secretase modulators.
The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.
Rivkin
Alexey
A
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. alexey_rivkin@merck.com
Ahearn
Sean P
SP
Chichetti
Stephanie M
SM
Hamblett
Christopher L
CL
Garcia
Yudith
Y
Martinez
Michelle
M
Hubbs
Jed L
JL
Reutershan
Michael H
MH
Daniels
Matthew H
MH
Siliphaivanh
Phieng
P
Otte
Karin M
KM
Li
Chaomin
C
Rosenau
Andrew
A
Surdi
Laura M
LM
Jung
Joon
J
Hughes
Bethany L
BL
Crispino
Jamie L
JL
Nikov
George N
GN
Middleton
Richard E
RE
Moxham
Christopher M
CM
Szewczak
Alexander A
AA
Shah
Sanjiv
S
Moy
Lily Y
LY
Kenific
Candia M
CM
Tanga
Flobert
F
Cruz
Jonathan C
JC
Andrade
Paula
P
Angagaw
Minilik H
MH
Shomer
Nirah H
NH
Miller
Thomas
T
Munoz
Benito
B
Shearman
Mark S
MS
D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051880:Receptors, Notch / Q000378:metabolism; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011687:Purines; D051880:Receptors, Notch; C538897:amyloid beta-protein (40-42); D053829:Amyloid Precursor Protein Secretases