Discovery of gamma-secretase inhibitors efficacious in a transgenic animal model of Alzheimer's disease.
Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.
Asberom
Theodros
T
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Zhao
Zhiqiang
Z
Bara
Thomas A
TA
Clader
John W
JW
Greenlee
William J
WJ
Hyde
Lynn A
LA
Josien
Hubert B
HB
Li
Wei
W
McPhail
Andrew T
AT
Nomeir
Amin A
AA
Parker
Eric M
EM
Rajagopalan
Murali
M
Song
Lixin
L
Wong
Gwendolyn T
GT
Zhang
Lili
L
Zhang
Qi
Q
Pissarnitski
Dmitri A
DA
D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D053829:Amyloid Precursor Protein Secretases