SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibition.
The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.
Rajapakse
Hemaka A
HA
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. hemaka_rajapakse@merck.com
Nantermet
Philippe G
PG
Selnick
Harold G
HG
Barrow
James C
JC
McGaughey
Georgia B
GB
Munshi
Sanjeev
S
Lindsley
Stacey R
SR
Young
Mary Beth
MB
Ngo
Phung L
PL
Holloway
M Katherine
MK
Lai
Ming-Tain
MT
Espeseth
Amy S
AS
Shi
Xiao-Ping
XP
Colussi
Dennis
D
Pietrak
Beth
B
Crouthamel
Ming-Chih
MC
Tugusheva
Katherine
K
Huang
Qian
Q
Xu
Min
M
Simon
Adam J
AJ
Kuo
Lawrence
L
Hazuda
Daria J
DJ
Graham
Samuel
S
Vacca
Joseph P
JP
D000588:Amines / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001224:Aspartic Acid / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000588:Amines; D004791:Enzyme Inhibitors; D001224:Aspartic Acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human