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Bioorg Med Chem Lett. 2015 Feb 1;25(3):668-72. doi: 10.1016/j.bmcl.2014.11.087. Epub 2014 Dec 6.

Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand.

Author information

1
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.
2
Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States.
3
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, United States.
4
Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Protein Studies Program, Oklahoma Medical Research Foundation, United States.
5
Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, United States; CoMentis Inc, Oklahoma City, OK 73104, United States.
6
CoMentis Inc, Oklahoma City, OK 73104, United States.
7
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.
8
Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, United States.
9
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.

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.

KEYWORDS:

Alzheimer’s disease; BACE-1; Memapsin 2; Protease inhibitors; β-secretase

PMID:
25537272
PMCID:
PMC4297543
DOI:
10.1016/j.bmcl.2014.11.087
[Indexed for MEDLINE]
Free PMC Article

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