title: Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand.
abstract: We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a-h) or a thiazole moiety (compounds 4a-e) as the P3 ligand. We have also explored Boc-β-amino-l-alanine as a novel P2 ligand. A number of inhibitors have displayed β-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, Ki=0.25nM, cellular EC50 of 194nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound β-secretase which revealed critical interactions in the active site.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States.
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, United States.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Yen
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Protein Studies Program, Oklahoma Medical Research Foundation, United States.
authors.forename: Xiangping
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, United States; CoMentis Inc, Oklahoma City, OK 73104, United States.
authors.forename: Thippeswamy
authors.initials: T
authors.lastname: Devasamudram
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, United States; CoMentis Inc, Oklahoma City, OK 73104, United States.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bilcer
authors.affiliation: CoMentis Inc, Oklahoma City, OK 73104, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Lei
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Protein Studies Program, Oklahoma Medical Research Foundation, United States; CoMentis Inc, Oklahoma City, OK 73104, United States.
authors.forename: Gerald
authors.initials: G
authors.lastname: Koelsch
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mesecar
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Protein Studies Program, Oklahoma Medical Research Foundation, United States; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, United States.
authors.forename: Jordan
authors.initials: J
authors.lastname: Tang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; C031280:pyrazole; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; BACE-1; Memapsin 2; Protease inhibitors; β-secretase