Macrocyclic BACE-1 inhibitors acutely reduce Aβ in brain after po application

Lerchner, Andreas; Machauer, Rainer; Betschart, Claudia; Veenstra, Siem J.; Rueeger, Heinrich; McCarthy, Clive; Tintelnot‐Blomley, Marina; Jaton, Anne-Lise; Rabe, Sabine; Desrayaud, Sandrine; Enz, Albert; Staufenbiel, Matthias; Paganetti, Paolo; Rondeau, Jean‐Michel; Neumann, Ulf

doi:10.1016/j.bmcl.2009.11.092

Cited by 57 publications

(51 citation statements)

References 18 publications

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“…BACE1 has a large active site, and it has been challenging to find compounds that cross the blood-brain barrier and are large enough to inhibit the active site without being broken down by endopeptidases (Huang et al 2009). However, some promising compounds have been reported to lower Ab levels in transgenic mice (Chang et al 2004;Hussain et al 2007;Fukumoto et al 2010;Lerchner et al 2010) and primates (Sankaranarayanan et al 2009), and human clinical trials are ensuing.…”

Section: Animal Models Of Alzheimer Diseasementioning

confidence: 99%

Animal Models of Alzheimer Disease

LaFerla

Green

2012

Cold Spring Harbor Perspectives in Medicine

346

210

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Section: Animal Models Of Alzheimer Diseasementioning

confidence: 99%

Animal Models of Alzheimer Disease

LaFerla

Green

2012

Cold Spring Harbor Perspectives in Medicine

346

210

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“…A cyclic peptide was prepared by attachment of two cysteines to the termini of the linear sequence followed by Fig. 8 Structures of some cyclic peptides that interfere with amyloidogenic signal transduction: (a) CP1R7K, (b) CP2W7K cyclic peptides discovered by screening chemical genetic drug candidates in vivo [108], (c) β-secretase inhibitor NB-544, and (d) macrocycleNB-216 [109,110] disulfide bond formation [114]. Using immunoprecipitation, Northern blotting, and cell viability assays, the cyclic peptide was shown to displace Aβ40 from the p75 NTR receptor, to inhibit the Aβ40-mediated signaling process, and to prevent Aβ40-mediated neuronal death in vitro [114].…”

Section: Transmembrane Neurotrophin P75 Receptor (P75 Ntr ) Antagonistmentioning

confidence: 99%

Anti-amyloidogenic Heterocyclic Peptides

Chemerovski-Glikman

Richman

Rahimipour

2016

Topics in Heterocyclic Chemistry

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The amyloid fibril is a highly ordered proteinous aggregate, originally discovered in the context of the self-assembly of soluble proteins into insoluble extracellular plaques. The molecular structure of amyloidosis, an energetically stable conformation with a thermodynamic local minimum, is of particular interest because of its possible pathogenicity. Amyloidogenic diseases (amyloidoses) are often fatal, widely heterogenic, and caused by sporadic, genetic, or infectious pathogens. Consequently, major effort has been directed in the past few decades to identify and develop agents that decrease the concentration of the pathogenic aggregates either by interfering with the self-assembly of the proteins or by modulating their physiological concentration. Heterocyclic peptides of natural and synthetic origin have gained special attention because of their demonstrated ability to interact with various amyloids. In addition to interfering with the amyloid aggregation process, many of the discovered peptides also inhibit the formation of fibrils, disassemble preformed fibrils, and prevent the pathogenic seeding effect. Others are instrumental candidates for passive vaccination against amyloid deposits. The promising preliminary results described here, together with the broad chemical diversity of heterocyclic peptides and their amenability to largescale production, make these compounds promising for anti-amyloidogenic research and for pharmacological therapy of amyloidoses.

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“…5,6 However, it has been shown that the pharmacokinetics of standard linear inhibitors can be significantly improved by cyclization, 7 and this approach has indeed been incorporated in the search for promising drug candidates in the field of AD research. Different methodologies to obtain these macrocycles have been used, such as metathesis, [8][9][10][11][12] reductive amination, 13 peptide coupling 9,14 and macrolactonization. 15 In this study, we describe the synthesis and biological evaluation of a series of macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere.…”

Section: Introductionmentioning

confidence: 99%

“…These P2 moieties have emerged as promising building blocks in earlier reported studies. 8,9,16 Also, a phenyl substituent was introduced in the macrocyclic ring in an attempt to reach into the S3 subpocket (S3sp) of the enzyme and thus improve the activity even further.…”

Section: Introductionmentioning

confidence: 99%

Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes

Sandgren

Agback

Johansson

et al. 2012

Bioorganic & Medicinal Chemistry

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A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or Nphenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC 50 values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyses were performed on selected compounds, and enzymeinhibitor interactions are discussed.

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Macrocyclic BACE-1 inhibitors acutely reduce Aβ in brain after po application

Cited by 57 publications

References 18 publications

Animal Models of Alzheimer Disease

Animal Models of Alzheimer Disease

Anti-amyloidogenic Heterocyclic Peptides

Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes

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