5,6-Diphenylpyridazine Derivatives as Acyl-CoA:Cholesterol Acyltransferase Inhibitors

Giovannoni, Maria Paola; Piaz, Vittorio Dal; Kwon, Byoung‐Mog; Kim, Mi Kyung; Kim, Young Kook; Toma, Lucio; Barlocco, Daniela; Bernini, Franco; Canavesi, M.

doi:10.1021/jm010807h

Cited by 24 publications

(21 citation statements)

References 25 publications

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“…For the pharmacophore modeling studies, a set of 46 ACAT inhibitors were selected from the literature (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and divided into a training set (21 molecules, Chart S1) and a test set (25 molecules, Chart S2) based on principles of structural diversity and wide coverage of the activity range (between 0.002 and 230 lM, six orders of magnitude). Structures of all compounds in this study were sketched using the Visualizer module of Discovery Studio 2.1.…”

Section: Preparation Of Data Setmentioning

confidence: 99%

Discovery of Novel Acyl Coenzyme A: Cholesterol Acyltransferase Inhibitors: Pharmacophore‐Based Virtual Screening, Synthesis and Pharmacology

et al. 2012

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The present study describes ligand-based pharmacophore modeling of a series of structurally diverse acyl coenzyme A cholesterol acyltransferase inhibitors. Quantitative pharmacophore models were generated using HypoGen module of Discovery Studio 2.1, whereby the best pharmacophore model possessing two hydrophobic, one ring aromatic, and one hydrogen bond acceptor feature for inhibition of acyl coenzyme A cholesterol acyltransferase showed a very good correlation coefficient (r = 0.942) along with satisfactory cost analysis. Hypo1 was also validated by test set and cross-validation methods. Developed models were found to be predictive as indicated by low error values for test set molecules. Virtual screening against Maybridge database using Hypo1 was performed. The two most potent compounds (47 and 48; predicted IC₅₀ = 1 nM) of the retrieved hits were synthesized and biologically evaluated. These compounds showed 86% and 88% inhibition of acyl coenzyme A cholesterol acyltransferase (at 10 μg/mL) with IC₅₀ value of 3.6 and 2.5 nM, respectively. As evident from the close proximity of biological data to the predicted values, it can be concluded that the generated model (Hypo1) is a reliable and useful tool for lead optimization of novel acyl coenzyme A cholesterol acyltransferase inhibitors.

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Section: Preparation Of Data Setmentioning

confidence: 99%

Discovery of Novel Acyl Coenzyme A: Cholesterol Acyltransferase Inhibitors: Pharmacophore‐Based Virtual Screening, Synthesis and Pharmacology

et al. 2012

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“…The first series involves 40 compounds displaying different inhibitory activity (range of 4 pIC 50 units) for the Acyl-CoA Cholesterol O-Acyl Transferase (ACAT) enzyme (see Tables 1-4) [25][26][27], which have received considerable attention owing to their cholesterol-lowering and antiatherosclerotic properties [28]. The second set of compounds corresponds to 14 agonists of the 5-hydroxytryptamine 3 receptor (5-HT 3 R; see Table 5), a member of a superfamily of ligand-gated ion channel receptors with potential therapeutic properties [29,30].…”

Section: Hydrophobic Similaritymentioning

confidence: 99%

Hydrophobic Molecular Similarity from MST Fractional Contributions to the Octanol/water Partition Coefficient

Munoz-Muriedas

Perspicace

Bech

et al. 2005

J Comput Aided Mol Des

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The use of a recently proposed hydrophobic similarity index for the alignment of molecules and the prediction of their differences in biological activity is described. The hydrophobic similarity index exploits atomic contributions to the octanol/water transfer free energy, which are evaluated by means of the fractional partitioning scheme developed within the framework of the Miertus-Scrocco-Tomasi continuum model. Those contributions are used to define global and local measures of hydrophobic similarity. The suitability of this computational strategy is examined for two series of compounds (ACAT inhibitors and 5-HT3 receptor agonists), which are aligned to maximize the global hydrophobic similarity using a Monte Carlo-simulated protocol. Indeed, the concept of local hydrophobic similarity is used to explore structure-activity relationships in a series of COX-2 inhibitors. Inspection of the 3D distribution of hydrophobic/hydrophilic contributions in the aligned molecules is valuable to identify regions of very similar hydrophobicity, which can define pharmacophoric recognition patterns. Moreover, low similar regions permit to identify structural elements that modulate the differences in activity between molecules. Finally, the quantitative relationships found between the pharmacological activity and the hydrophobic similarity index points out that not only the global hydrophobicity, but its 3D distribution, is important to gain insight into the activity of molecules.

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“…This can be readily realized from vast number of papers and patents dealing with synthesis [1][2][3][4][5] , chemistry [6][7][8] , and biological activities of pyridazine derivatives 9,10 . In the last few years we have been involved in a programme aimed at developing efficient syntheses of pyridazines and fused pyridazines [11][12][13][14] utilizing functionally substituted arylhydrazones precursors.…”

Section: Introductionmentioning

confidence: 99%

Functionally substituted arylhydrazones as building blocks in heterocyclic synthesis: routes to pyridazines and pyridazinoquinazolines

Ghozlan¹,

Abdelhamid²,

Elnagdi³

2006

Arkivoc

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The arylhydrazones 2a-c were prepared via coupling acetoacetic acid with aromatic diazonium salts. These arylhydrazones condensed with ethyl cyanoacetate and malononitrile to yield the acyclic product 4 which cyclised only after long reflux into the pyridazines 5 or 6,11-dihydropyridazino[1,6-a]quinazoline-4-carbonitrile 6 depending on the nature of substituent on the aryl moiety. Compound 2b and 2c reacted with α,β-unsaturatednitriles 7 to yield the pyridazinoquinazoline 13 and 16 respectively.

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5,6-Diphenylpyridazine Derivatives as Acyl-CoA:Cholesterol Acyltransferase Inhibitors

Cited by 24 publications

References 25 publications

Discovery of Novel Acyl Coenzyme A: Cholesterol Acyltransferase Inhibitors: Pharmacophore‐Based Virtual Screening, Synthesis and Pharmacology

Discovery of Novel Acyl Coenzyme A: Cholesterol Acyltransferase Inhibitors: Pharmacophore‐Based Virtual Screening, Synthesis and Pharmacology

Hydrophobic Molecular Similarity from MST Fractional Contributions to the Octanol/water Partition Coefficient

Functionally substituted arylhydrazones as building blocks in heterocyclic synthesis: routes to pyridazines and pyridazinoquinazolines

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