Identification of pharmacophore model, synthesis and biological evaluation of N-phenyl-1-arylamide and N-phenylbenzenesulfonamide derivatives as BACE 1 inhibitors.
The pharmacophore model of arylpiperazine amide derivatives was built using Discovery Studio 2.0 software package and the best pharmacophore model (Hypo 1) was validated by Enrichment and ROC method (EF at 2%, 5% and 10% are 30.6, 12.2 and 7.7; AUC of the ROC curve is 0.93). According to the best pharmacophore model, 11 N-phenyl-1-arylamide, N-phenylbenzenesulfonamide derivatives, compounds 26-28, and 33a-g, were designed to be synthesized and their BACE 1 inhibitory activities were determined experimentally. Their theoretical results were in good agreement with the experimental values. Compound 33d, which displayed the highest BACE 1 activity (18.33+/-2.80 micromol/L) among these two series, was chosen to study the protein binding pattern and the result showed that it was in close contact with two essential catalytic aspartates (Asp32 and Asp228) of the BACE 1.
Huang
Wenhai
W
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, Zijingang Campus, Hangzhou 310058, China.
Yu
Haiping
H
Sheng
Rong
R
Li
Jia
J
Hu
Yongzhou
Y
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human