Aminoimidazoles as BACE-1 inhibitors: The challenge to achieve in vivo brain efficacy

Swahn, Britt‐Marie; Holenz, Jörg; Kihlström, J. E.; Kolmodin, Karin; Lindström, Johan; Plobeck, Niklas; Rotticci, Didier; Sehgelmeble, Fernando W.; Sundström, Marie; Fälting, Johanna; Georgievska, Biljana; Gustavsson, Susanne; Neelissen, Jan; Ek, Margareta; Olsson, Lars‐Inge; Berg, Stefan von

doi:10.1016/j.bmcl.2012.01.079

Cited by 47 publications

(47 citation statements)

References 19 publications

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“…hBACE1 and hBACE2 Time-resolved-FRET Assay-The procedure used has been described elsewhere (37). In short, the soluble part of the human ␤-secretase (recombinant hBACE1 enzyme, amino acids 1-460, or hBACE2 enzyme, amino acids 1-473) was mixed with compound in reaction buffer (sodium acetate, CHAPS, Triton X-100, EDTA, pH 4.5) and preincubated for 10 min.…”

Section: Methodsmentioning

confidence: 99%

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Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease

Jeppsson

Eketjäll

Janson

et al. 2012

Journal of Biological Chemistry

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120

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Section: Methodsmentioning

confidence: 99%

“…SH-SY5Y A␤40 Release Assay-The procedure used has been described elsewhere (37). In short, SH-SY5Y cells overexpressing APP695wt were cultured in DMEM/F-12 with Glutamax, 10% FCS, and 1% nonessential amino acids (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease

Jeppsson

Eketjäll

Janson

et al. 2012

Journal of Biological Chemistry

Self Cite

120

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“…Further optimization provided compound 122 showing a low nanomolar inhibitor with a pIC 50 value of 7.5. 268 When dosed orally in wild type mice, compound 122 , a decrease of brain Aβ 40 levels of 17% 1.5 hours post dose. Compound 123 , with a spirocyclic cyclobutane moiety, showed an IC 50 of 10 nM.…”

Section: Nonpeptide Inhibitorsmentioning

confidence: 99%

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

2014

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BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's Disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's Disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials.

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“…Compound 45 (Fig. 9) (pIC 50 = 7.50) was selected for evaluation in vivo and, 1.5 h after oral co-administration of 300 μmol/kg 45 and efflux inhibitor GF120918, the brain Aβ40 level was reduced by 17% and the plasma Aβ40 level by 76% [91]. …”

Section: Small-molecule β-Secretase Inhibitorsmentioning

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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Aminoimidazoles as BACE-1 inhibitors: The challenge to achieve in vivo brain efficacy

Cited by 47 publications

References 19 publications

Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease

Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

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

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Aminoimidazoles as BACE-1 inhibitors: The challenge to achieve in vivo brain efficacy

Cited by 47 publications

References 19 publications

Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease

Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

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