Piperazinyl pyrimidine derivatives as potent gamma-secretase modulators.
The development of a novel series of piperazinyl pyrimidines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a screening hit provided a series of potent gamma-secretase modulators with >180-fold in vitro selectivity over inhibition of Notch cleavage.
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
Kim
Yoona R
YR
Li
Chaomin
C
Rosenau
Andrew
A
Kattar
Sam D
SD
Jung
Joon
J
Shah
Sanjiv
S
Hughes
Bethany L
BL
Crispino
Jamie L
JL
Middleton
Richard E
RE
Szewczak
Alexander A
AA
Munoz
Benito
B
Shearman
Mark S
MS
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010879:Piperazines; D011743:Pyrimidines; C538897:amyloid beta-protein (40-42); D053829:Amyloid Precursor Protein Secretases