Design and synthesis of a second series of triazole-based compounds as potent dual mPGES-1 and 5-lipoxygenase inhibitors

Chini, Maria Giovanna; Simone, R. De; Bruno, Ines; Riccio, Raffaele; Dehm, Friederike; Weinigel, Christina; Barz, Dagmar; Werz, Oliver; Bifulco, Giuseppe

doi:10.1016/j.ejmech.2012.05.014

Cited by 40 publications

(14 citation statements)

References 45 publications

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“…In addition, several specific modifications to this chemical structure have been reported by Giroux et al [123] that enhance oral bioavailability and improve the pharmacokinetic profile. More recently, as part of a highly comprehensive study, Chini et al [124] have reported promising results with respect to the design and synthesis of a new generation of drugs based on the triazole scaffold that provide dual inhibition of both mPGES-1 and 5-lipoxygenase, offering the promise of safer and more effective anti-inflammatory agents. Finally, Beales and Ogunwobi [125] demonstrated with the use of either RNA interference or a small molecule inhibitor (CAY10526) the inhibition of esophogeal adenocarcinoma growth in cell culture.…”

Section: Drug Targeting Of Mpges-1 For Cancer Suppressionmentioning

confidence: 99%

Multifaceted roles of PGE2 in inflammation and cancer

2012

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Prostaglandin E2 (PGE2) is a bioactive lipid that elicits a wide range of biological effects associated with inflammation and cancer. PGE2 exerts diverse effects on cell proliferation, apoptosis, angiogenesis, inflammation and immune surveillance. This review concentrates primarily on gastrointestinal cancers, where the actions of PGE2 are most prominent, most likely due to the constant exposure to dietary and environmental insults and the intrinsic role of PGE2 in tissue homeostasis. A discussion of recent efforts to elucidate the complex and interconnected pathways that link PGE2 signaling with inflammation and cancer is provided, supported by the abundant literature showing a protective effect of NSAIDs and the therapeutic efficacy of targeting mPGES-1 or EP receptors for cancer prevention. However, suppressing PGE2 formation as a means of providing chemoprotection against all cancers may not ultimately be tenable, undoubtedly the situation for patients with inflammatory bowel disease. Future studies to fully understand the complex role of PGE2 in both inflammation and cancer will be required to develop novel strategies for cancer prevention that are both effective and safe.

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Section: Drug Targeting Of Mpges-1 For Cancer Suppressionmentioning

confidence: 99%

Multifaceted roles of PGE2 in inflammation and cancer

2012

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“…The further design of analogs from one of these compounds has allowed the identification of benzo[ d ]isothiazole 1,1‐dioxide as suitable skeleton for the generation of dual mPGES‐1/5‐LOX inhibitors . In addition, analogs of 2‐mercaptohexanoic acid, triazole, and 2‐benzylidenehexanoic acid have been synthesized, providing promising compounds with dual inhibitory action against mPGES‐1 and 5‐LOX . Despite the encouragement yielded by the results gathered until now, further preclinical and clinical data are necessary to eventually support the use of mPGES‐1/5‐LOX in anti‐inflammatory therapy.…”

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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“…Moving the electron donating methyl residue in ortho position at the benzyloxy moiety to para position resulted in a steric hindrance and caused a loss of bioactivity (34). When the methyl residue was replaced by an electron-withdrawing chlorine (36) or trifluoromethyl (37), the potency in cell-based assays slightly improved (IC 50 ¼ 0.77e1.4 mM) but in the cell-free assay the activity was impaired (IC 50 ¼ 5.9e6.1 mM).…”

Section: Biological Evaluation and Sar Studiesmentioning

confidence: 98%

“…The unavailability of a holo 5-LO conformation represented the first major difficulty to elucidate the ligand-active site interactions. Therefore, we referred to the conserved or unconserved active site interaction models [33,34]. Grounding on those results, we combined docking studies with MD simulations (see Supporting information for detail) to investigate the binding mode of inhibitors taking into account ligand-induced conformational changes of 5-LO.…”

Section: Docking Studies and Molecular Dynamic (Md) Simulations With mentioning

confidence: 99%