A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl pirinixic acid scaffold

Hieke, Martina; Thieme, Theresa M.; Schubert‐Zsilavecz, Manfred; Werz, Oliver; Zettl, Heiko

doi:10.1016/j.bmcl.2011.01.049

Cited by 18 publications

(9 citation statements)

References 13 publications

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“…For instance, the substitution of the carboxylic acid moiety of indomethacin, lonazolac, and licofelone by sulfonamide moieties allowed the synthesis of potent dual acting compounds without cross‐reactivity on COX . Moreover, diverse series of pirinixic acid derivatives were designed and evaluated regarding the dual inhibition of mPGES‐1 and 5‐LOX, namely, α‐substituted derivatives, α‐naphtyl derivatives and 2‐aminothiazole derivatives . Among the various pirinixic acid derivatives with dual acting activity, one α‐(n‐hexyl)‐substituted derivative (YS121) and one 2‐aminothiazole derivative have exhibited anti‐inflammatory actions in vivo .…”

Section: Identification Of Novel Targets In the Arachidonic Acid Cascadementioning

confidence: 99%

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

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Section: Identification Of Novel Targets In the Arachidonic Acid Cascadementioning

confidence: 99%

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Pereira-Leite

Nunes

Jamal

et al. 2016

Medicinal Research Reviews

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“…The dataset of 59 structurally diverse compounds with nonredox 5‐LO inhibitory activities ( IC 50 ) in cell‐free systems was selected from the literature 10–26. The IC 50 values were converted into corresponding p IC 50 values by the formula p IC 50 =−log( IC 50 ), where IC 50 represents the half maximal (50 %) inhibitory concentration of a molecule.…”

Section: Methodsmentioning

confidence: 99%

From Molecular Docking to 3D‐Quantitative Structure‐Activity Relationships (3D‐QSAR): Insights into the Binding Mode of 5‐Lipoxygenase Inhibitors

Eren

Macchiarulo

Banoğlu

2012

Molecular Informatics

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Pharmacological intervention with 5-Lipoxygenase (5-LO) is a promising strategy for treatment of inflammatory and allergic ailments, including asthma. With the aim of developing predictive models of 5-LO affinity and gaining insights into the molecular basis of ligand-target interaction, we herein describe QSAR studies of 59 diverse nonredox-competitive 5-LO inhibitors based on the use of molecular shape descriptors and docking experiments. These studies have successfully yielded a predictive model able to explain much of the variance in the activity of the training set compounds while predicting satisfactorily the 5-LO inhibitory activity of an external test set of compounds. The inspection of the selected variables in the QSAR equation unveils the importance of specific interactions which are observed from docking experiments. Collectively, these results may be used to design novel potent and selective nonredox 5-LO inhibitors.

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“…. Further development of this scaffold led to potency optimization . The approach of privileged structures was also followed by Elkady et al .…”

Section: Approved Drugsmentioning

confidence: 99%

Inhibitors of the Arachidonic Acid Cascade: Interfering with Multiple Pathways

Meirer

Steinhilber

Proschak

2013

Basic Clin Pharma Tox

111

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Modulators of the arachidonic acid cascade have been in the focus of research for treatments of inflammation and pain for several decades. Targeting this complex pathway experiences a paradigm change towards the design and development of multi-target inhibitors, exhibiting improved efficacy and less undesired side effects. This minireview summarizes recent developments in the field of designed multi-target ligands of the arachidonic acid cascade. In addition to the well-known dual inhibitors of 5-lipoxygenase and cyclooxygenase-2 such as licofelone, very recent developments are discussed. Especially, multi-target inhibitors interfering with the cytochrome P450 pathway via inhibition of soluble epoxide hydrolase seem to offer a novel opportunity for development of novel anti-inflammatory drugs.

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A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl pirinixic acid scaffold

Cited by 18 publications

References 13 publications

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

From Molecular Docking to 3D‐Quantitative Structure‐Activity Relationships (3D‐QSAR): Insights into the Binding Mode of 5‐Lipoxygenase Inhibitors

Inhibitors of the Arachidonic Acid Cascade: Interfering with Multiple Pathways

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