Pyridinyl aminohydantoins as small molecule BACE1 inhibitors.
A novel class of pyridinyl aminohydantoins was designed and prepared as highly potent BACE1 inhibitors. Compound (S)-4g showed excellent potency with IC(50) of 20 nM for BACE1. X-ray crystallography indicated that the interaction between pyridine nitrogen and the tryptophan Trp76 was a key feature in the S2' region of the enzyme that contributed to increased potency.
Zhou
Ping
P
Department of Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, United States. zhoupb31@gmail.com
Li
Yanfang
Y
Fan
Yi
Y
Wang
Zheng
Z
Chopra
Rajiv
R
Olland
Andrea
A
Hu
Yun
Y
Magolda
Ronald L
RL
Pangalos
Menelas
M
Reinhart
Peter H
PH
Turner
M James
MJ
Bard
Jonathan
J
Malamas
Michael S
MS
Robichaud
Albert J
AJ
D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D006827:Hydantoins; D011725:Pyridines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human