Acylguanidines as Small-Molecule β-Secretase Inhibitors

Cole, Derek C.; Manas, Eric S.; Stock, Joseph R.; Condon, Jeffrey S.; Jennings, Lee D.; Aulabaugh, Ann; Chopra, Rajiv; Cowling, Rebecca; Ellingboe, John W.; Fan, Kristi; Harrison, Boyd L.; Hu, Yun; Jacobsen, Steve; Jin, Guixian; Lin, Laura; Lovering, Frank; Malamas, Michael S.; Stahl, Mark; Strand, James; Sukhdeo, Mohani N.; Svenson, Kristine; Turner, M. James; Wagner, Erik; Wu, Junjun; Zhou, and Ping; Bard, Jonathan

doi:10.1021/jm0607451

Cited by 105 publications

(73 citation statements)

References 27 publications

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“…A data set of 78 compounds as the inhibitors of b-secretase derived from Cole et al (2006Cole et al ( , 2008, Jennings et al (2008) and Malamas et al (2010) was employed in this study. Inhibitory concentrations (IC 50 ) of these compounds were transformed to negative logarithmic units marked as pIC 50 .…”

Section: Data Setmentioning

confidence: 99%

“…Recently, a series of acylguanidines of b-secretase inhibitors was discovered and synthetized (Cole et al, 2006Jennings et al, 2008). To cross the blood-brain barrier of the acylguanidines, a series of novel pyrrolyl 2-aminopyridines with the lower total polar surface area (TPSA) was designed according to the biososterism (Malamas et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Study on the active mechanism of β-secretase inhibitors by molecular simulations

Tian

et al. 2015

European Journal of Pharmaceutical Sciences

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Section: Data Setmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Study on the active mechanism of β-secretase inhibitors by molecular simulations

Tian

et al. 2015

European Journal of Pharmaceutical Sciences

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“…Wyeth reported on a novel class of BACE-1 inhibitors that are markedly different than the traditional transition state-based inhibitor series [Cole et al, 2006]. A high-throughput screen identified the acylguanidine 15 as a potential hit with an IC 50 value of 3.7 mM against BACE-1.…”

Section: Acylguanidines As Small Molecule Bace-1 Inhibitorsmentioning

confidence: 99%

Progress toward the development of a viable BACE‐1 inhibitor

Stachel¹

2009

Drug Development Research

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Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive formation of insoluble amyloid plaque and fibrillary tangles. Plaques are extracellular constructs consisting primarily of Ab 42 derived from the catabolism of b-amyloid precursor protein (APP). b-Secretase (BACE-1) is the enzyme responsible for the initiatory cleavage event in APP catabolism. The central role of BACE-1 in the production of Ab 42 has made it an attractive target for drug development. However, the development of BACE-1 inhibitors has been hampered by difficulty in identifying inhibitors with acceptable pharmacokinetic and CNS penetration properties. The maturation of the BACE-1 drug discovery effort from typical peptidomimetic inhibitors to more novel structural classes is reviewed. Drug Dev

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“…Another class of non-peptidic BACE1 inhibitors were obtained from a highthroughput screening (HTS) technology-based assay targeting chemical libraries. Typical examples of this class of inhibitors include compounds 10d [26] , 3a [27] , and TAK-070 [28] , which are orally active and show good selectivity over other aspartic proteases. The third class of BACE1 inhibitors includes natural products, such as catechins obtained from Green tea [29] , lavandulyl flavanones extracted from Sophora flavescens [30] , resveratrol obtained from Vitis vinifera [31] and TDC obtained from Glycyrrhiza glabra [32] .…”

Section: Introductionmentioning

confidence: 99%

L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases β-amyloid peptide production in HEK293-APPswe cells

et al. 2012

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Aim: To identify a small molecule L655,240 as a novel β-secretase (BACE1) inhibitor and to investigate its effects on β-amyloid (Aβ) generation in vitro. Methods: Fluorescence resonance energy transfer (FRET) was used to characterize the inhibitory effect of L655,240 on BACE1. Surface plasmon resonance (SPR) technology-based assay was performed to study the binding affinity of L655,240 for BACE1. The selectivity of L655,240 toward BACE1 over other aspartic proteases was determined with enzymatic assay. The effects of L655,240 on Aβ40, Aβ42, and sAPPβ production were studied in HEK293 cells stably expressing APP695 Swedish mutant K595N/M596L (HEK293-APPswe cells). The activities of BACE1, γ-secretase and α-secretase were assayed, and both the mRNA and protein levels of APP and BACE1 were evaluated using real-time PCR (RT-PCR) and Western blot analysis. Results: L655,240 was determined to be a competitive, selective BACE1 inhibitor (IC 50 =4.47±1.37 μmol/L), which bound to BACE1 directly (K D =17.9±0.72 μmol/L). L655,240 effectively reduced Aβ40, Aβ42, and sAPPβ production by inhibiting BACE1 without affecting the activities of γ-secretase and α-secretase in HEK293-APPswe cells. L655,240 has no effect on APP and BACE1 mRNA or protein levels in HEK293-APPswe cells. Conclusion:The small molecule L655,240 is a novel BACE1 inhibitor that can effectively decreases Aβ production in vitro, thereby highlighting its therapeutic potential for the treatment of Alzheimer's disease.

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Acylguanidines as Small-Molecule β-Secretase Inhibitors

Cited by 105 publications

References 27 publications

Study on the active mechanism of β-secretase inhibitors by molecular simulations

Study on the active mechanism of β-secretase inhibitors by molecular simulations

Progress toward the development of a viable BACE‐1 inhibitor

L655,240, acting as a competitive BACE1 inhibitor, efficiently decreases β-amyloid peptide production in HEK293-APPswe cells

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