Effect of Some Biologically Interesting Substituted Tetrahydro-1,4- Oxazines on Drug Metabolising Enzymes and on Inflammation

Rekka, Eleni A.; Kourounakis, Angeliki P.; Avramidis, Nicholaos; Kourounakis, Panos N.

doi:10.2174/138920005774330648

Cited by 6 publications

(3 citation statements)

References 26 publications

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“…Pharmacological characterization of these derivatives was further extended and they were shown to reduce acute inflammatory response in two inflammation models while inhibiting lipoxygenase in vitro [125,128] They also significantly increased the accumulation of eNOS in cultured bovine aortic and calf pulmonary arterial endothelial cells [129]. Thus, in combination with their NOdonating capacity, these molecules may confer protective effects to the vasculature [128].…”

Section: Morpholinesmentioning

confidence: 99%

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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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Section: Morpholinesmentioning

confidence: 99%

“…Thus, in combination with their NOdonating capacity, these molecules may confer protective effects to the vasculature [128].…”

Section: Morpholinesmentioning

confidence: 99%

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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“…αµίδια, σε αναλογία και µε τη δράση τους στη λιποξυγονάση. Έτσι, αυτές οι ενώσεις είναι ικανές να προσφέρουν προστασία έναντι των ελευθέρων ριζών τόσο µε άµεση αναστολή της λιπιδικής υπεροξείδωσης όσο και µέσω της επίδρασης τους στη λιποξυγονάση, η οποία θεωρείται ότι παίζει σηµαντικό ρόλο στη δηµιουργία οξειδωτικού stress σε κυτταρικό επίπεδο [Rekka EA et al 2005].…”

Section: εκτίµηση της αντιοξειδωτικής ικανότητας των ενώσεωνunclassified

Σύγχρονες Προσεγγίσεις Στο Σχεδιασμό Και Στην Ανάπτυξη Αντιφλεγμονωδών Ενώσεων

Ζιάκας¹

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οξέος (τολφαιναµικού οξέος) µε τις αντίστοιχες νιτροοξυαλκοόλες…………………………...86 4.1.2.2. Σύνθεση των αµινών και αµιδίων παραγώγων της 2,6 δι-t-βουτυλοφαινόλης….88 4.2. ΕΛΕΓΧΟΙ ∆ΡΑΣΗΣ...………………………………………………………….…...92 4.2.1. In vivo προσδιορισµοί…………………………………….………………….…...92 4.2.1.1. Εκτίµηση της αντιφλεγµονώδους δράσης των τελικών ενώσεων από την αναστολή πρόκλησης οιδήµατος από καρραγενίνη……………………………………...92 4.2.1.2. Εκτίµηση της τοξικότητας στο γαστρεντερικό σύστηµα………………………..92 4.2.1.3. Εκτίµηση της γενικής τοξικότητας των ενώσεων…………………………….....93 4.2.2. In vitro προσδιορισµοί……….…………………...……………………………….93 4.2.2.1. Εκτίµηση της αντιοξειδωτικής δράσης των τελικών ενώσεων……….…………93 4.2.2.1.1. In vitro λιπιδική υπεροξείδωση…………………….…………………………93 4.2.2.1.2. Αλληλεπίδραση των τελικών ενώσεων µε την 1,1-διφαινυλο-2πικρυλυδραζυλο σταθερή ελεύθερη ρίζα (DPPH)………………………….……………94 4.2.2.2. Εκτίµηση της αντιφλεγµονώδους δράσης των τελικών ενώσεων….……...…....94 4.2.2.2.1. Επίδραση των ενώσεων στη δραστηριότητα της λιποξυγονάσης….………….94 4.2.2.2.2. Επίδραση των τελικών ενώσεων στην δραστηριότητα των ισοµορφών 1 και 2 της κυκλοοξυγονάσης……..……………………………………………………………..95 10 4.2.2.3. Προσδιορισµός της ικανότητας απελευθέρωσης µονοξειδίου του αζώτου από τα παράγωγα νιτροεστέρων του τολφαιναµικού οξέος……………………………………..95 4.3. ΟΡΓΑΝΑ ΑΝΤΙ∆ΡΑΣΤΗΡΙΑ ΚΑΙ ΠΕΙΡΑΜΑΤΟΖΩΑ………………….

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Simulation of NMR chemical shifts in heterocycles: a method evaluation

Buß

Koch

2016

J Mol Model

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An alternative approach to evaluating the performance of computational methods for predicting chemical shifts is presented. The influence of the theoretical level and basis set on the accuracy in calculating both proton and carbon NMR spectra of a large number of heterocyclic molecules is assessed using a linear regression method, thus omitting the need for a reference (as a potential source of error). The best theoretical levels employed herein (GIAO-PBE0/6-31G(d)//ωB97xD/6-31G(d) or GIAO-ωB97xD/6-31G(d)//ωB97xD/6-31G(d)) approach the accuracy of the most elaborate benchmark-quality calculations. One interesting observation is an unexplained distortion of the derived chemical shifts when an internal reference is used: It leads to larger relative shifts and deviations when the "quality" (size) of the basis set employed is increased. This effect can be corrected by using simple linear regression, but a lack of a systematic correlation between the quality of the basis set and the accuracy of the calculated shifts can still be observed; in fact, very good results can be achieved with modest basis sets. Although the general reliability of this approach needs to be evaluated for other theoretical levels and other substance classes, the abovementioned levels of theory appear robust enough for wider applicability. Graphical Abstract Correlation between computed chemical shieldings and experimental chemical shifts for various heterocyclic compounds.

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Effect of Some Biologically Interesting Substituted Tetrahydro-1,4- Oxazines on Drug Metabolising Enzymes and on Inflammation

Cited by 6 publications

References 26 publications

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

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

Σύγχρονες Προσεγγίσεις Στο Σχεδιασμό Και Στην Ανάπτυξη Αντιφλεγμονωδών Ενώσεων

Simulation of NMR chemical shifts in heterocycles: a method evaluation

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