Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation.
A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.
Stauffer
Shaun R
SR
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. shaun_stauffer@merck.com
Stanton
Matthew G
MG
Gregro
Alison R
AR
Steinbeiser
Melissa A
MA
Shaffer
Jennifer R
JR
Nantermet
Philippe G
PG
Barrow
James C
JC
Rittle
Kenneth E
KE
Collusi
Dennis
D
Espeseth
Amy S
AS
Lai
Ming-Tain
MT
Pietrak
Beth L
BL
Holloway
M Katharine
MK
McGaughey
Georgia B
GB
Munshi
Sanjeev K
SK
Hochman
Jerome H
JH
Simon
Adam J
AJ
Selnick
Harold G
HG
Graham
Samuel L
SL
Vacca
Joseph P
JP
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D016367:Baculoviridae / Q000187:drug effects / Q000201:enzymology; D001682:Biological Availability; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008970:Molecular Weight; D009536:Niacinamide / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009536:Niacinamide; C027681:isonicotinamide; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human