Identification and optimization of tetrahydro-2H-3-benzazepin-2-ones as squalene synthase inhibitors

Griebenow, Nils; Flessner, Timo; Buchmueller, Anja; Raabe, Martin; Bischoff, Hilmar; Kolkhof, Peter

doi:10.1016/j.bmcl.2011.02.004

Cited by 19 publications

(9 citation statements)

References 14 publications

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“…A set of 34 compounds tested with the same assay has been collected from different references . The compounds cover diverse structures and the molecular bioactivities in IC 50 ranging from 0.59 to 3300 nM.…”

Section: Methodsmentioning

confidence: 99%

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Identification of hit compounds for squalene synthase: Three‐dimensional quantitative structure‐activity relationship pharmacophore modeling, virtual screening, molecular docking, binding free energy calculation, and molecular dynamic simulation

Hou

Yan

Ma³

et al. 2017

Journal of Chemometrics

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Squalene synthase (SQS) is the key precursor in the synthesis of cholesterol. Located downstream in relation to hydroxy methylglutaryl coenzyme A reductase and having no influence on the formation of biologically necessary isoprenoids make it an interesting target for the development of cholesterol lowering drugs with fewer side effects. To discover novel SQS inhibitors, three-dimensional quantitative structure-activity relationship pharmacophore models were built and further validated by cost function analysis, test set validation, and decoy set validation to obtain a reliable model for virtual screening against a database that contains 5.5 million compounds. The interactions between SQS and the ligands were predicted by an integrated protocol that contains molecular docking, molecular mechanics/generalized born surface area, and molecular dynamic simulation. After that, five compounds with best binding affinities and binding modes were obtained as potential hits for further study and three of them showed inhibitory effects against SQS.KEYWORDS binding free energy, molecular dynamic simulation, pharmacophore model, SQSIs, virtual screening Manzhou Hou and Guoyi Yan contributed equally to this work.

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Section: Methodsmentioning

confidence: 99%

“…In recent years, the population of arteriosclerosis, ischemic heart diseases, and ischemic brain diseases attributed to arteriosclerosis, which is the most common reason of morbidity and mortality in developed countries, is growing in the world because of the spread of the western dietary pattern and the increasing number of older people …”

Section: Introductionmentioning

confidence: 99%

Identification of hit compounds for squalene synthase: Three‐dimensional quantitative structure‐activity relationship pharmacophore modeling, virtual screening, molecular docking, binding free energy calculation, and molecular dynamic simulation

Hou

Yan

Ma³

et al. 2017

Journal of Chemometrics

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“…In the first, Griebenow et al [151] at Bayer disclosed novel potent tetrahydro-2H-3-benzazepine-2-ones (e.g. 98) (Fig.…”

Section: Recent Studiesmentioning

confidence: 98%

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

Kourounakis

Katselou²,

Matralis³

et al. 2011

CMC

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Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.

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“…18. 71 All the compounds prepared in the study possess a core structure adorned with a chiral 1,1diaryl motif. Structurally related to lapaquistat, these novel compounds have too been shown to be potent squalene synthase inhibitors and the best compound is undergoing further pharmacological study.…”

Section: Antihypertensivesmentioning

confidence: 99%

“…Structurally related to lapaquistat, these novel compounds have too been shown to be potent squalene synthase inhibitors and the best compound is undergoing further pharmacological study. 71…”

Section: Antihypertensivesmentioning

confidence: 99%

Chiral 1,1-diaryl compounds as important pharmacophores

2013

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Identification and optimization of tetrahydro-2H-3-benzazepin-2-ones as squalene synthase inhibitors

Cited by 19 publications

References 14 publications

Identification of hit compounds for squalene synthase: Three‐dimensional quantitative structure‐activity relationship pharmacophore modeling, virtual screening, molecular docking, binding free energy calculation, and molecular dynamic simulation

Identification of hit compounds for squalene synthase: Three‐dimensional quantitative structure‐activity relationship pharmacophore modeling, virtual screening, molecular docking, binding free energy calculation, and molecular dynamic simulation

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

Chiral 1,1-diaryl compounds as important pharmacophores

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