4-substituted cyclohexyl sulfones as potent, orally active gamma-secretase inhibitors.
The protease gamma-secretase plays a pivotal role in the synthesis of pathogenic amyloid-beta in Alzheimer's disease (AD). Here, we report a further extension to a series of cyclohexyl sulfone-based gamma-secretase inhibitors which has allowed the preparation of highly potent compounds which also demonstrate robust Abeta(40) lowering in vivo (e.g., compound 32, MED 1mg/kg p.o. in APP-YAC mice).
Churcher
Ian
I
Department of Medicinal Chemistry, The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. ian_churcher@merck.com
Beher
Dirk
D
Best
Jonathan D
JD
Castro
José L
JL
Clarke
Earl E
EE
Gentry
Amy
A
Harrison
Timothy
T
Hitzel
Laure
L
Kay
Euan
E
Kerrad
Sonia
S
Lewis
Huw D
HD
Morentin-Gutierrez
Pablo
P
Mortishire-Smith
Russell
R
Oakley
Paul J
PJ
Reilly
Michael
M
Shaw
Duncan E
DE
Shearman
Mark S
MS
Teall
Martin R
MR
Williams
Susie
S
Wrigley
Jonathan D J
JD
D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000187:drug effects; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003510:Cyclohexanes / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D010446:Peptide Fragments / Q000187:drug effects; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D013450:Sulfones; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse