Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: Prime side chromane-containing inhibitors

Ng, Raymond; Sun, Minghua; Bowers, Simeon; Hom, Roy K.; Probst, Gary D.; John, Varghese; Fang, Lawrence Y.; Maillard, Michel; Gailunas, Andrea; Brogley, Louis; Neitz, R. Jeffrey; Tung, Jay S.; Pleiss, Michael A.; Konradi, Andrei W.; Sham, Hing L.; Dappen, Michael S.; Adler, Marc; Yao, Nanhua; Zmolek, Wes; Nakamura, David; Quinn, Kevin P.; Sauer, John‐Michael; Bova, Michael P.; Ruslim, Lany; Artis, Dean R.; Yednock, Ted

doi:10.1016/j.bmcl.2013.06.006

Cited by 11 publications

(6 citation statements)

References 28 publications

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“…Further investigation resulted in inhibitors such as 60 , 61 , and 62 . 180 Unfortunately, inhibitors 60 and 61 showed more potent inhibitory activity against cathepsin D than BACE1. Compound 62 showed modest selectivity, however it did not show promising cell membrane permeability.…”

Section: Design Of Peptidomimetic Bace1 Inhibitorsmentioning

confidence: 98%

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: Design Of Peptidomimetic Bace1 Inhibitorsmentioning

confidence: 98%

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

2014

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“…Since its identification in 1999, BACE1 has attracted a significant amount of attention as a potential target for the development of an AD therapy. BACE1 contains a long, shallow, and hydrophilic active site, and early efforts to identify BACE1 inhibitors produced large, polar compounds with unfavorable physicochemical properties and consequently poor pharmacokinetics and central nervous system (CNS) penetration . More recently, a number of groups have described BACE1 inhibitors that employ a 2-aminoheterocycle which engages in hydrogen bonding interactions with the catalytic aspartic acid residues of the protease .…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)

et al. 2014

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We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Aβ levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.

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“…The developed 2D-QSAR models for AChE and BACE-1 inhibitors were built upon the data curated from CheMBL database [ 60 ], and reported literatures [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. The data was processed appropriately according to the guidelines of OECD (Organization for Economic Co-operation and Development) for an acceptable QSAR model [ 73 ] (further details are provided in the Materials and Methods section).…”

Section: Resultsmentioning

confidence: 99%

“…The dataset of AChE inhibitors was obtained from CheMBL database [ 60 ], and the BACE-1 inhibitor database was collected from reported literatures [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. Initial processing of input data was then carried out, including rejecting substances with similar structures (use Cluster codes tool in MOE 2008.10 [ 84 ]), retaining compounds with the same bioassay method, and correcting IC 50 appropriately.…”

Section: Methodsmentioning

confidence: 99%

Synthesis, In Silico and In Vitro Evaluation for Acetylcholinesterase and BACE-1 Inhibitory Activity of Some N-Substituted-4-Phenothiazine-Chalcones

Thai

Nguyen

et al. 2020

Molecules

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Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are two attractive targets in the discovery of novel substances that could control multiple aspects of Alzheimer’s disease (AD). Chalcones are the flavonoid derivatives with diverse bioactivities, including AChE and BACE-1 inhibition. In this study, a series of N-substituted-4-phenothiazine-chalcones was synthesized and tested for AChE and BACE-1 inhibitory activities. In silico models, including two-dimensional quantitative structure–activity relationship (2D-QSAR) for AChE and BACE-1 inhibitors, and molecular docking investigation, were developed to elucidate the experimental process. The results indicated that 13 chalcone derivatives were synthesized with relatively high yields (39–81%). The bioactivities of these substances were examined with pIC50 3.73–5.96 (AChE) and 5.20–6.81 (BACE-1). Eleven of synthesized chalcones had completely new structures. Two substances AC4 and AC12 exhibited the highest biological activities on both AChE and BACE-1. These substances could be employed for further researches. In addition to this, the present study results suggested that, by using a combination of two types of predictive models, 2D-QSAR and molecular docking, it was possible to estimate the biological activities of the prepared compounds with relatively high accuracy.

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Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: Prime side chromane-containing inhibitors

Cited by 11 publications

References 28 publications

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

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

Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)

Synthesis, In Silico and In Vitro Evaluation for Acetylcholinesterase and BACE-1 Inhibitory Activity of Some N-Substituted-4-Phenothiazine-Chalcones

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