Potent pyrrolidine- and piperidine-based BACE-1 inhibitors

Iserloh, Ulrich; Wu, Yusheng; Cumming, Jared N.; Pan, Jianping; Wang, L.Y.; Stamford, Andrew W.; Kennedy, Matthew; Kuvelkar, Reshma; Chen, X.; Parker, Eric M.; Strickland, Corey; Voigt, Johannes H.

doi:10.1016/j.bmcl.2007.10.116

Cited by 79 publications

(52 citation statements)

References 20 publications

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“…Inhibitor 44 (GSK 188909) showed potent inhibitory activity (IC 50 = 2 nM) and reduced brain Ab levels in TASTPM mice via oral administration. The researchers at Schering-Plough (merged with Merck in 2009) reported non-peptidic inhibitors 45 and 46 (IC 50 = 21 and 3 nM, respectively) with an isophthalamide scaffold, as shown in Figure 4D [91][92][93]. Inhibitor 45 also showed plasma Ab level via oral administration in transgenic CRND8 mice.…”

Section: Non-peptidic Bace1 Inhibitors By Structure-based Designmentioning

confidence: 92%

Advances in the identification of β-secretase inhibitors

Hamada

Kiso

2013

Expert Opinion on Drug Discovery

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Many BACE1 inhibitors have been designed using X-ray crystal structure-based drug design as well as through in silico screening. Nevertheless, there are serious problems with regards to deciding the best X-ray crystal structure for designing BACE1 inhibitors through computational approaches. There are two prominent configurations of BACE1 but there is still room for improvement. Future developments may make it possible to identify BACE1 inhibitors as potential drug candidates.

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Section: Non-peptidic Bace1 Inhibitors By Structure-based Designmentioning

confidence: 92%

Advances in the identification of β-secretase inhibitors

Hamada

Kiso

2013

Expert Opinion on Drug Discovery

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“…A high resolution (1.50 Å) crystallographic structure of human -secretase in complex with SC7 was reported by Iserloh et al 12 The 3D structure was retrieved from the PDB and analyzed inhibitor binding site residues. The residues such as Gly72, Gln73, Leu91, Asp93, Gly95, Ser96, Pro131, Tyr132, Thr133, Gln134, Gly135, Lys168, Phe169, Ile171, Trp176, Tyr259, Ile287, Asp289, Gly291, Thr292, Thr293 and Arg295 were observed to be present within 4Å region of SC7 (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…12 The inhibitor binding site of -secretase was determined through analysis of 2QP8 using PyMOL, an open viewer molecular software. 13 The protein preparation wizard of Schrodinger 2011 was used to prepare the protein.…”

Section: Protein Preparationmentioning

confidence: 99%

Identification of potent inhibitors for β-secretase through structure based virtual screening and molecular dynamics simulations

Mobeen¹,

Pradhan²,

Priyadarshini³

et al. 2013

JCSR

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Background: Alzheimer's disease (AD) is a neurodegenerative disorder in elderly persons aged above 65 years. The cleavage of amyloid precursor protein (APP) by -secretase generates peptide fragment A42, the main cause of memory and cognitive defects in AD. Therefore, elevated level of -secretase results in accumulation of insoluble form of A peptides (senile plaques) representing the protein as an attractive drug target of AD. Methods:Five recently reported -secretase antagonist (thiazolidinediones, rosiglitazone, pioglitazone, SC7 and tartaric acid) structural analogs were searched from ligand info database and prepared using LigPrep. The crystal structure of -secretase was optimized using Maestro v9.2 protein preparation wizard applying optimized potential for liquid simulations (OPLS)-2005 force field. Structure based virtual screening was performed for -secretase from prepared ligands using virtual screening workflow of Maestro v9.2 and was ranked based on XP Gscore.Results: Eight lead molecules were identified to have better binding affinity (lower XP Gscore) compared to five existing -secretase antagonists and appear to have good pharmacological properties. Binding orientations of the lead molecules were in well agreement with existing inhibitors. Lead1 showed lowest XP Gscore (-10.72 Kcal/mol). Molecular dynamics (MD) simulations of -secretase-lead1 complex was stable in all trajectories. Conclusion:Lead1 is proposed as potent inhibitor of -secretase and thus could be considered for rational drug design against AD.

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“…Through biological evaluation, the compounds were found to exhibit excellent inhibitory effects and cell-permeability [24] . According to these results, many other inhibitors with high potency were also obtained by combining the substituted isopthalamides into the HEA scaffold [25,26] . However, until now, no compound bearing the HEA scaffold has gone to clinical trial.…”

Section: Introductionmentioning

confidence: 99%

“…An N-methyl(methylsulfonyl)amino, nitro or hydrogen group was incorporated at the 5-position as R 2 . All designed groups of R 3 and R 2 were selected according to our previous studies and those by Merck's group [25,26,28] and combined several analogues, such as 4-fluorobenzyl and benzyl moieties at the 3-position, for systematically investigating the SAR of these types of inhibitors.…”

Section: Chemistrymentioning

confidence: 99%

Discovery of potent β-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids

Zhu

Xiao

et al. 2009

Acta Pharmacol Sin

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Aim:The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease β-secretase (BACE-1) bearing hydroxyethylene (HE) framework.Methods: First, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode. Results:Thirteen new compounds (6-18) have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance (NMR) spectra, low-and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study. Conclusion:This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer's disease.

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Potent pyrrolidine- and piperidine-based BACE-1 inhibitors

Cited by 79 publications

References 20 publications

Advances in the identification of β-secretase inhibitors

Advances in the identification of β-secretase inhibitors

Identification of potent inhibitors for β-secretase through structure based virtual screening and molecular dynamics simulations

Discovery of potent β-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids

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