Identification of a sub-micromolar, non-peptide inhibitor of β-secretase with low neural cytotoxicity through in silico screening.

Nowadays identification of novel non-peptide β-secretase (BACE-1, hereinafter) inhibitors with low cytotoxicity and good blood-brain barrier (BBB) property holds common interest of drug discovery for Alzheimer's disease. Twenty SPECS compounds were tested in BACE-1 FRET assays and methylthiazoletetrazolium (MTT) cytotoxicity experiment. Two compounds: 2 and 15 demonstrated IC(50) values of 0.53 and 9.4 μM. In addition, 2 showed least toxic effect to the neuroblastoma cells. The results from both in silico and in vitro studies provided new pharmacophoric entities for chemical synthesis and optimization on the current discovered BACE-1 small molecule inhibitors.

[1]  I. Melnikova.  Therapies for Alzheimer's disease , 2007, Nature Reviews Drug Discovery.

[2]  Matthew S. Johnson,et al.  Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors. , 2009, Journal of medicinal chemistry.

[3]  P. Jeffrey,et al.  Oral administration of a potent and selective non‐peptidic BACE‐1 inhibitor decreases β‐cleavage of amyloid precursor protein and amyloid‐β production in vivo , 2007 .

[4]  Alison R. Gregro,et al.  Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). , 2004, Journal of medicinal chemistry.

[5]  Weiliang Zhu,et al.  Novel non-peptide beta-secretase inhibitors derived from structure-based virtual screening and bioassay. , 2009, Bioorganic & medicinal chemistry letters.

[6]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[7]  Paul Zuck,et al.  Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase. , 2008, Journal of medicinal chemistry.

[8]  W. Pardridge,et al.  CNS Drug Design Based on Principles of Blood‐Brain Barrier Transport , 1998, Journal of neurochemistry.

[9]  H. Cai,et al.  BACE1 is the major β-secretase for generation of Aβ peptides by neurons , 2001, Nature Neuroscience.

[10]  C. Haass,et al.  The cell biology of Alzheimer's disease: uncovering the secrets of secretases , 2001, Current Opinion in Neurobiology.

[11]  Claire Mount,et al.  Alzheimer disease: progress or profit? , 2006, Nature Medicine.

[12]  Gianni Chessari,et al.  Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of beta-secretase. , 2007, Journal of medicinal chemistry.

[13]  Jean-Michel Rondeau,et al.  Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors. , 2009, Bioorganic & medicinal chemistry letters.

[14]  Yongzhou Hu,et al.  Progress in the development of nonpeptidomimetic BACE 1 inhibitors for Alzheimer's disease. , 2009, Current medicinal chemistry.

[15]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[16]  Junya Qu,et al.  2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead. , 2007, Journal of medicinal chemistry.