Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors

Cumming, Jared N.; Le, Thuy X.; Babu, Suresh; Carroll, Carolyn DiIanni; Chen, X.; Favreau, Leonard; Gaspari, Paul; Guo, Tao; Hobbs, Doug W.; Huang, Ying; Iserloh, Ulrich; Kennedy, Matthew; Kuvelkar, Reshma; Li, G.; Lowrie, Jayme; McHugh, Nansie A.; Ozgur, Lynne; Pan, Jianping; Parker, Eric M.; Saionz, Kurt W.; Stamford, Andrew W.; Strickland, Corey; Tadesse, Dawit; Voigt, Johannes H.; Wang, Liming; Wu, Yusheng; Zhang, L.; Zhang, Q.

doi:10.1016/j.bmcl.2008.04.050

Cited by 60 publications

(24 citation statements)

References 24 publications

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“…Inhibitor 44 (GSK 188909) showed potent inhibitory activity (IC 50 = 2 nM) and reduced brain Ab levels in TASTPM mice via oral administration. The researchers at Schering-Plough (merged with Merck in 2009) reported non-peptidic inhibitors 45 and 46 (IC 50 = 21 and 3 nM, respectively) with an isophthalamide scaffold, as shown in Figure 4D [91][92][93]. Inhibitor 45 also showed plasma Ab level via oral administration in transgenic CRND8 mice.…”

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

confidence: 91%

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: 91%

Advances in the identification of β-secretase inhibitors

Hamada

Kiso

2013

Expert Opinion on Drug Discovery

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“…Many other examples of similarly constrained hydroxyethylamine inhibitors have been reported in patent literatures. 204-210 …”

Section: Design Of Peptidomimetic Bace1 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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“…PK studies showed overall good pharmacological properties although permeability was low, with a brain/plasma ratio < 0.1, making it unlikely to be efficacious for AD treatment. The further X-ray structure-guided modifications of substituted piperidine derivatives that was aimed to improve interaction with Thr72 of the flap region resulted in the discovery of piperazinine and imidazolidinone classes of BACE-1 inhibitors, with low nanomolar potency in vitro and submicromolar potency in cellular assays [64]. These compounds showed a modest decrease of A plasma levels in the CRND8 mice, but no effect on A brain levels, due to low brain penetration.…”

Section: Heterocyclic Hea Derivativesmentioning

confidence: 98%

BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

Evin¹,

Lessène²,

Wilkins

2011

RPCN

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Current drug development for the treatment of Alzheimer's Disease is principally based on the amyloid cascade theory, and aims to reduce the levels of Aβ amyloid peptide in the brain. This can be achieved, either by decreasing peptide production through inhibition of β-secretase (also known as BACE-1) or γ-secretase, or by interfering with Aβ aggregation, or by promoting Aβ clearance. Targeting BACE-1, the proteolytic enzyme that initiates Aβ formation, has generated a lot of research interest recently and is currently thought to be one of the most promising therapeutic approaches. In this review, we summarize and discuss the latest patents and publications describing BACE-1 inhibitors, principally focussing on their drug properties and performance in preclinical trials.

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Rational design of novel, potent piperazinone and imidazolidinone BACE1 inhibitors

Cited by 60 publications

References 24 publications

Advances in the identification of β-secretase inhibitors

Advances in the identification of β-secretase inhibitors

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

BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

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