Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1).
We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.
Rajapakse
Hemaka A
HA
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. hemaka_rajapakse@merck.com
Nantermet
Philippe G
PG
Selnick
Harold G
HG
Munshi
Sanjeev
S
McGaughey
Georgia B
GB
Lindsley
Stacey R
SR
Young
Mary Beth
MB
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
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry
D000814:Aniline Compounds; D010069:Oxadiazoles; D053829:Amyloid Precursor Protein Secretases