Discovery and initial optimization of 5,5′-disubstituted aminohydantoins as potent β-secretase (BACE1) inhibitors

Nowak, Paweł; Cole, Derek C.; Aulabaugh, Ann; Bard, Jonathan; Chopra, Rajiv; Cowling, Rebecca; Fan, Kristi; Hu, Baihua; Jacobsen, Steve; Jani, Minakshi; Jin, Guixian; Lo, Mei-Chu; Malamas, Michael S.; Manas, Eric S.; Narasimhan, Rani; Reinhart, Peter H.; Robichaud, Albert J.; Stock, Joseph R.; Subrath, Joan; Svenson, Kristine; Turner, James; Wagner, Erik; Zhou, Ping; Ellingboe, John W.

doi:10.1016/j.bmcl.2009.11.052

Cited by 28 publications

(10 citation statements)

References 23 publications

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“…Based upon high throughput hit, compound 126 was developed. 277 This inhibitor had a BACE1 IC 50 of 40 nM and was 427-fold more potent for BACE1 than cathepsin D. Unfortunately, compound 126 was slightly more potent for BACE2 than BACE1, with a BACE2 IC 50 of 30 nM. The aminohydantoin scaffold has been further explored with a variety of functionalities extending from phenyl rings to biaryl rings.…”

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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Section: Nonpeptide Inhibitorsmentioning

confidence: 99%

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

2014

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“…The binding site predicted to be deep within the binding pocket was consistent with mutagenesis studies. QXP has been used to optimize inhibitors of human b-secretase (BACE1) (Malamas et al, 2009(Malamas et al, , 2010Nowak et al, 2010), which is an important therapeutic target for treating Alzheimer's disease by diminishing b-amyloid deposit formation. ICM was used successfully to identify inhibitors for a number of targets, including tumor necrosis factor-a (Chan et al, 2010), dysregulation of which is implicated in tumorigenesis and autoinflammatory diseases like Computational Methods in Drug Discovery rheumatoid arthritis and psoriatic arthritis.…”

Section: Sampling Algorithms For Protein-ligand Dockingmentioning

confidence: 99%

Computational Methods in Drug Discovery

et al. 2013

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“…Aminohydantoin 56, in which a part of the rings of 55 is truncated, shows a 10-fold higher potency (IC 50 = 3.4 µM). Furthermore, the potent BACE1 inhibitor 57 (WY-258131, IC 50 = 10 nM) was designed by their SAR study [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126]. However, in in vivo experiments using animal models, these inhibitors showed weak efficacy in lowering Ab levels in the brain.…”

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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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Discovery and initial optimization of 5,5′-disubstituted aminohydantoins as potent β-secretase (BACE1) inhibitors

Cited by 28 publications

References 23 publications

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

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

Computational Methods in Drug Discovery

Advances in the identification of β-secretase inhibitors

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