A conformational constraint improves a β-secretase inhibitor but for an unexpected reason

Hills, Ivory D.; Holloway, M. Katharine; León, Pablo de; Nomland, Ashley; Zhu, Haifei; Rajapakse, Hemaka A.; Allison, Tim J.; Munshi, Sanjeev; Colussi, Dennis; Pietrak, Beth; Toolan, Dawn; Haugabook, Sharie J.; Graham, Samuel; Stachel, Shawn J.

doi:10.1016/j.bmcl.2009.07.071

Cited by 17 publications

(14 citation statements)

References 18 publications

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“…Compound 117 , displayed good enzyme inhibitory potency and showed low Pgp efflux ratio of 3.6. 264 Compound 118 showed a BACE1 IC 50 of 7.4 μM. 265 A modeling study of this compound in the BACE1 active site suggested that the amino group hydrogen bonds to the catalytic aspartic acid residues while the unsubstituted N3 nitrogen of the imidazole ring makes electrostatic and hydrogen bonding interactions with the side chains of Asp228 and Asp32 (Figure 56).…”

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 replacement of the 1-aminothiazole moiety in 63 with an N-methyl-amino-imidazole group improved the inhibitory activity in a cell-based assay (64, BACE1 IC 50 = 0.47 µM, cell IC 50 = 1.8 µM). Inhibitor 65, which was again cyclized in the central part, showed improved inhibitory activity (IC 50 = 63 nM) and P-gp efflux ratio (B-A:A-B = 3.6) [128,129]. The last hit compound, inhibitor 66, had an IC 50 value of 317 µM.…”

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confidence: 94%

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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“…In recent years BACE-1 has been a primary target for Aβ lowering therapies, however the development of bio-available inhibitors has been a major challenge so far 25 , and only a few molecules have advanced to clinical trials. The fact that in our study we can block Sp1-dependent transcription of BACE1 by using a pharmacological inhibitor of 12-15LO suggests that selective blockade of this enzyme could be a novel disease-modifying therapeutic approach for the treatment or prevention of AD.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of βsecretase‐1 by 12/15‐lipoxygenase results in enhanced amyloidogenesis and cognitive impairments

Chu

Zhuo

Praticò

2012

Annals of Neurology

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Objective The 12-15Lipoxygenase (12-15LO) is an enzyme widely distributed in the central nervous system and it has been involved in the neurobiology of Alzheimer’s disease (AD). However, the mechanism involved remains elusive. Methods We investigated the molecular mechanism by which 12-15LO regulates Amyloid β/APP metabolism in vivo and in vitro by genetic and pharmacologic approaches. Results Here we show that over-expression of 12-15LO leads to increased levels of BACE1 mRNA and protein, a significant elevation in Aβ levels and deposition, and a worsening of memory deficits in AD transgenic mice. In vitro and in vivo studies demonstrate that 12-15LO regulates BACE1 mRNA expression levels via the activation of the transcription factor Sp1. Thus, 12-15LO-overexpressing mice had elevated levels of Sp1 and BACE1, whereas 12/15LO-deficient mice had reduced levels of both. Preventing Sp1 activation by pharmacologic inhibition or dominant negative mutant blocks the 12-15LO-dependent elevation of Aβ and BACE1 levels. Interpretation Our findings demonstrate a novel pathway by which 12-15LO increases the amyloidogenic processing of APP through a Sp1-mediated transcriptional control of BACE1 levels that could have implications for AD pathogenesis and therapy.

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A conformational constraint improves a β-secretase inhibitor but for an unexpected reason

Cited by 17 publications

References 18 publications

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

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

Advances in the identification of β-secretase inhibitors

Transcriptional regulation of βsecretase‐1 by 12/15‐lipoxygenase results in enhanced amyloidogenesis and cognitive impairments

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