Recent progress in the drug discovery of non-peptidic BACE1 inhibitors

Hamada, Y.; Kiso, Yoshiaki

doi:10.1517/17460440902806377

Cited by 49 publications

(24 citation statements)

References 62 publications

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“…[12][13][14][15] BACE1 is a membrane protein found primarily in the brain and is a member of the pepsin family under the aspartyl protease superfamily. BACE1 shares sequence homology with BACE2 (52%), cathepsin D (29%), pepsin (27%), cathepsin E (27%), and renin (24%).…”

Section: 11mentioning

confidence: 99%

Docking and Quantitative Structure Activity Relationship studies of Acyl Guanidines as β-Secretase (BACE1) Inhibitor

Hwang

Im²

2014

Bulletin of the Korean Chemical Society

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β-Secretase (beta-amyloid converting enzyme 1 [BACE1]) is involved in the first and rate-limiting step of β-amyloid (Aβ) peptides production, which leads to the pathogenesis of Alzheimer's disease(AD). Therefore, inhibition of BACE1 activity has become an efficient approach for the treatment of AD. Ligand-based and docking-based 3D-quantitative structure-activity relationship (3D-QSAR) studies of acyl guanidine analogues were performed with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to obtain insights for designing novel potent BACE1 inhibitors. We obtained highly reliable and predictive CoMSIA models with a cross-validated q 2 value of 0.725 and a predictive coefficient r 2 pred value of 0.956. CoMSIA contour maps showed the structural requirements for potent activity. 3D-QSAR analysis suggested that an acyl guanidine and an amide group in the R 6 substituent would be important moieties for potent activity. Moreover, the introduction of small hydrophobic groups in the phenyl ring and hydrogen bond donor groups in 3,5-dichlorophenyl ring could increase biological activity.

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Section: 11mentioning

confidence: 99%

Docking and Quantitative Structure Activity Relationship studies of Acyl Guanidines as β-Secretase (BACE1) Inhibitor

Hwang

Im²

2014

Bulletin of the Korean Chemical Society

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“…Furthermore, selectivity for inhibition of BACE1 over related aspartyl proteases, such as BACE2 and cathepsin-D, was an additional constraint imposed on potential clinical candidates, in light of the antagonistic amyloidogenic activity of BACE2 (Farzan et al 2000;Yan et al 2001;Fluhrer et al 2002;Basi et al 2003) and the essential role of cathepsin-D in lysosomal function (Saftig et al 1996;Benes et al 2008). The interested reader is directed to expert medicinal chemistry reviews for structure -activity relationship studies toward the objectives of CNS-active, BACE1-selective, drug-like inhibitors (Hussain 2004;Thompson et al 2005;Durham and Shepherd 2006;John 2006;Ziora et al 2006;Ghosh et al 2008;Silvestri 2008;Hamada and Kiso 2009;Stachel 2009). Incompatibility between MW constraints (imposed by potency requirements) and size (for CNS permeability) have proven to be significant challenges in overcoming the p-gylcoproteinmediated efflux of BACE1 inhibitors from the CNS and has slowed advancement into the clinic of the many research efforts that were launched to discover and develop BACE inhibitors for treatment of AD.…”

Section: Bace Inhibitorsmentioning

confidence: 99%

Treatment Strategies Targeting Amyloid -Protein

Schenk¹,

Basi²,

Pangalos

2012

Cold Spring Harbor Perspectives in Medicine

108

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With the advent of the key discovery in the mid-1980s that the amyloid b-protein (Ab) is the core constituent of the amyloid plaque pathology found in Alzheimer disease (AD), an intensive effort has been underway to attempt to mitigate its role in the hope of treating the disease. This effort fully matured when it was clarified that the Ab is a normal product of cleavage of the amyloid precursor protein, and well-defined proteases for this process were identified. Further therapeutic options have been developed around the concept of anti-Ab aggregation inhibitors and the surprising finding that immunization with Ab itself leads to reduction of pathology in animal models of the disease. Here we review the progress in this field toward the goal of targeting Ab for treatment and prevention of AD and identify some of the major challenges for the future of this area of medicine.

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“…Pns possessing nonpeptidic and smallsized derivatives exhibited no BACE-1 inhibitory activity. KMI-1027 and KMI-1036 with a heterocyclic ring at the P 2 position and a five-membered ring at the P 3 position are expected to be practical anti-Alzheimers disease drug candidates [214,215]. Despite the promising results, the actual effects of BACE-1 inhibitors for Alzheimers disease patients need to be further evaluated.…”

Section: Bace-1 Inhibitorsmentioning

confidence: 99%