title: Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Srinivas Reddy
authors.initials: SR
authors.lastname: Chirapu
authors.forename: Boobalan
authors.initials: B
authors.lastname: Pachaiyappan
authors.forename: Hikmet F
authors.initials: HF
authors.lastname: Nural
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.forename: David C
authors.initials: DC
authors.lastname: Lankin
authors.forename: Samer O
authors.initials: SO
authors.lastname: Abdul-Hay
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
authors.forename: Yong
authors.initials: Y
authors.lastname: Shen
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Petukhov
mesh_terms: 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
chemical_list: 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