Fluorinated piperidine acetic acids as gamma-secretase modulators.
We report herein a novel series of difluoropiperidine acetic acids as modulators of gamma-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective beta-difluorination with Selectfluor. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Abeta42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250mg/kg per day, AUC(0-24)=2100microMh) did not exhibit Notch-related effects.
Stanton
Matthew G
MG
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. matthew_stanton@merck.com
Hubbs
Jed
J
Sloman
David
D
Hamblett
Christopher
C
Andrade
Paula
P
Angagaw
Minilik
M
Bi
Grace
G
Black
Regina M
RM
Crispino
Jamie
J
Cruz
Jonathan C
JC
Fan
Eric
E
Farris
Georgia
G
Hughes
Bethany L
BL
Kenific
Candia M
CM
Middleton
Richard E
RE
Nikov
George
G
Sajonz
Peter
P
Shah
Sanjiv
S
Shomer
Nirah
N
Szewczak
Alexander A
AA
Tanga
Flobert
F
Tudge
Matthew T
MT
Shearman
Mark
M
Munoz
Benito
B
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003979:Diazonium Compounds / Q000737:chemistry; D004195:Disease Models, Animal; D005461:Fluorine / Q000737:chemistry*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism
D000085:Acetates; D016229:Amyloid beta-Peptides; D003979:Diazonium Compounds; D010446:Peptide Fragments; D010880:Piperidines; D051880:Receptors, Notch; C075222:amyloid beta-protein (1-42); D005461:Fluorine; C408750:selectfluor; D053829:Amyloid Precursor Protein Secretases