Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids.
OBJECTIVE
The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease beta-secretase (BACE-1) bearing hydroxyethylene (HE) framework.


METHODS
First, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode.


RESULTS
Thirteen new compounds (6-18) have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance (NMR) spectra, low- and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study.


CONCLUSIONS
This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer's disease.
Zhu
Yi-Ping
YP
The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Xiao
Kun
K
Yu
Hai-Ping
HP
Ma
Lan-Ping
LP
Xiong
Bing
B
Zhang
Hai-Yan
HY
Wang
Xin
X
Li
Jing-Ya
JY
Li
Jia
J
Shen
Jing-Kang
JK
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000577:Amides / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010795:Phthalic Acids / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D000577:Amides; C520858:GRL 7234; D007527:Isoenzymes; D010795:Phthalic Acids; D011480:Protease Inhibitors; D013449:Sulfonamides; C059768:isophthalate; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D014633:Valine