Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

Rueeger, Heinrich; Lueoend, Rainer; Rogel, Olivier; Rondeau, Jean‐Michel; Möbitz, Henrik; Machauer, Rainer; Jacobson, Laura H.; Staufenbiel, Matthias; Desrayaud, Sandrine; Neumann, Ulf

doi:10.1021/jm300069y

Cited by 89 publications

(59 citation statements)

References 101 publications

(84 reference statements)

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“…Inhibitor 48 showed potent inhibition in cultured cells and reduced plasma Ab levels in wild-type and P-gp knockout mice. The researchers at Novartis reported a series of non-peptidic BACE1 inhibitors (e.g., 49, IC 50 = 2 nM, Figure 4E) [97,98]. Although they designed 49 using the classical structure-based approach, it is notable that 49 has a unique cyclic scaffold at the P 1 position.…”

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

confidence: 99%

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: 99%

Advances in the identification of β-secretase inhibitors

Hamada

Kiso

2013

Expert Opinion on Drug Discovery

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“…In the past decades, many X-ray structures of the apo BACE1 and the BACE1-inhibitor complex have been deter-www.nature.com/aps Wang YY et al Acta Pharmacologica Sinica npg mined, which provide detailed information about the structure and functional analysis of BACE1 [11][12][13][14][15][16] . BACE1 is a membraneanchored aspartic protease containing three distinct domains: an N-terminal ectodomain, a single transmembrane domain, and a cytosolic C-terminus.…”

Section: Introductionmentioning

confidence: 99%

Microsecond molecular dynamics simulation of Aβ42 and identification of a novel dual inhibitor of Aβ42 aggregation and BACE1 activity

Wang

Chen

et al. 2013

Acta Pharmacol Sin

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Aim: To study the conformational changes of Aβ 42 and discover novel inhibitors of both Aβ 42 aggregation and β-secretase (BACE1). Methods: A molecular dynamics (MD) simulation at a microsecond level was performed to explore stable conformations of Aβ 42 monomer in aqueous solution. Subsequently, structure-based virtual screening was used to search for inhibitors of both Aβ 42 aggregation and BACE1. Protein purification and in vitro activity assays were performed to validate the inhibition of the compounds identified via virtual screening. Results: The initial α-helical conformation of Aβ 42 , which was unstable in aqueous solution, turned into a β-sheet mixed with a coil structure through a transient and fully random coil. The conformation of Aβ 42 mainly comprising β-sheets and coils structure was used for further virtual screening. Five compounds were identified as inhibitors for Aβ 42 aggregation, and one of them, AE-848, was discovered to be a dual inhibitor of both Aβ 42 aggregation and BACE1, with IC 50 values of 36.95 μmol/L and 22.70 μmol/L, respectively. Conclusion: A helical to β-sheet conformational change in Aβ 42 occurred in a 1.8 microsecond MD simulation. The resulting β-sheet structure of the peptide is an appropriate conformation for the virtual screening of inhibitors against Aβ 42 aggregation. Five compounds were identified as inhibitors of Aβ 42 aggregation by in vitro activity assays. It was particularly interesting to discover a dual inhibitor that targets both Aβ 42 aggregation and BACE1, the two crucial players in the pathogenesis of Alzheimer's disease.

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“…6) with enzymatic and cellular IC 50 values of 2 and 50 nM, respectively, and with >200-fold selectivity over CatD. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated a significant reduction of brain Aβ levels [70, 71]. …”

Section: Bioisosteric Morphing Of Early Transition State Isostere-mentioning

confidence: 99%

The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

Butini¹,

Brogi²,

Novellino³

et al. 2013

CTMC

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Effective treatment of Alzheimer’s disease (AD) remains a critical unmet need in medicine. The lack of useful treatment for AD led to an intense search for novel therapies based on the amyloid hypothesis, which states that amyloid β-42 (Aβ42) plays an early and crucial role in all cases of AD. β-Secretase (also known as BACE-1 β-site APP-cleaving enzyme, Asp-2 or memapsin-2) is an aspartyl protease representing the rate limiting step in the generation of Aβ peptide fragments, therefore it could represent an important target in the steady hunt for a disease-modifying treatment. Generally, β-secretase inhibitors are grouped into two families: peptidomimetic and nonpeptidomimetic inhibitors. However, irrespective of the class, serious challenges with respect to blood–brain barrier (BBB) penetration and selectivity still remain. Discovering a small molecule inhibitor of β-secretase represents an unnerving challenge but, due to its significant potential as a therapeutic target, growing efforts in this task are evident from both academic and industrial laboratories. In this frame, the rising availability of crystal structures of β-secretase-inhibitor complexes represents an invaluable opportunity for optimization. Nevertheless, beyond the inhibitory activity, the major issue of the current research approaches is about problems associated with BBB penetration and pharmacokinetic properties. This review follows the structural evolution of the early β-secretase inhibitors and gives a snap-shot of the hottest chemical templates in the literature of the last five years, showing research progress in this field.

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Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

Cited by 89 publications

References 101 publications

Advances in the identification of β-secretase inhibitors

Advances in the identification of β-secretase inhibitors

Microsecond molecular dynamics simulation of Aβ42 and identification of a novel dual inhibitor of Aβ42 aggregation and BACE1 activity

The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

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Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

Cited by 89 publications

References 101 publications

Advances in the identification of β-secretase inhibitors

Advances in the identification of β-secretase inhibitors

Microsecond molecular dynamics simulation of Aβ42 and identification of a novel dual inhibitor of Aβ42 aggregation and BACE1 activity

The Structural Evolution of &#946;-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors

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The Structural Evolution of β-Secretase Inhibitors: A Focus on the Development of Small-Molecule Inhibitors