Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase.
A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.
Barrow
James C
JC
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. james_barrow@merck.com
Stauffer
Shaun R
SR
Rittle
Kenneth E
KE
Ngo
Phung L
PL
Yang
ZhiQiang
Z
Selnick
Harold G
HG
Graham
Samuel L
SL
Munshi
Sanjeev
S
McGaughey
Georgia B
GB
Holloway
M Katharine
MK
Simon
Adam J
AJ
Price
Eric A
EA
Sankaranarayanan
Sethu
S
Colussi
Dennis
D
Tugusheva
Katherine
K
Lai
Ming-Tain
MT
Espeseth
Amy S
AS
Xu
Min
M
Huang
Qian
Q
Wolfe
Abigail
A
Pietrak
Beth
B
Zuck
Paul
P
Levorse
Dorothy A
DA
Hazuda
Daria
D
Vacca
Joseph P
JP
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D048289:Imidazolidines; D010880:Piperidines; D053829:Amyloid Precursor Protein Secretases