Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors.
A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand 5b reduced 65% of Abeta40 production in N2a cells stably transfected with Swedish human APP.
Chirapu
Srinivas Reddy
SR
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
Pachaiyappan
Boobalan
B
Nural
Hikmet F
HF
Cheng
Xin
X
Yuan
Hongbin
H
Lankin
David C
DC
Abdul-Hay
Samer O
SO
Thatcher
Gregory R J
GR
Shen
Yong
Y
Kozikowski
Alan P
AP
Petukhov
Pavel A
PA
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008024:Ligands; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human