Development of 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E2 synthase-1 inhibitors

Banerjee, Abhisek; Pawar, Mahesh Y.; Patil, Saiprasad; Yadav, Pravin; Kadam, Pradip A.; Kattige, Vidya G.; Deshpande, D. S.; Pednekar, Pallavi V.; Pisat, Monali; Gharat, Laxmikant A.

doi:10.1016/j.bmcl.2014.08.056

Cited by 30 publications

(7 citation statements)

References 30 publications

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“…1D). Thus, the considerable cardiovascular side effects of celecoxib could be circumvented by using this celecoxib derivative [29]. Notably, we found that DMC obtained stronger cytotoxicity than celecoxib when applied in combination with ABT-737 in GC cells, which was consistent with previous published studies [17].…”

Section: Discussionsupporting

confidence: 92%

Dimethyl celecoxib sensitizes gastric cancer cells to ABT‐737 via AIF nuclear translocation

Zhang

Yan

et al. 2016

J Cellular Molecular Medi

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Gastric cancer is the fourth most common cancer in the world. The clinical applications of both chemotherapy and targeted drugs are limited because of the complexity of gastric cancer. In this study, sulforhodamine B, colony formation assay, 4',6‐diamidino‐2‐phenylindole (DAPI) stain, flow cytometry were used to determine the in vitro cytotoxicity, apoptosis and mitochondrial membrane potential of gastric cancer AGS and HGC‐27 cells before and after treatment. Real‐time PCR and Western blot were used to analyse the mRNA transcription and protein expression respectively. Confocal microscopy was used to determine the localization of target protein within the cells. Treatment with the combination of ABT‐737 and 2,5‐dimethyl‐celecoxib (DMC) showed strong synergistic effect in both AGS and HGC‐27 cells. Moreover, DMC would not influence the intracellular prostaglandin E2 (PGE2) level, thus lacking the toxicity profile of celecoxib. Interestingly, given the significant synergistic effect, combination treatment did not affect the protein expression of BH‐3 proteins including Puma, Noxa and Bim. In combination treatment, cell apoptosis was found independent of caspase‐3 activation. The translocation of apoptosis‐inducing factor (AIF) from mitochondrion to nuclear was responsible for the induced apoptosis in the combination treatment. Taken together, this study provided a novel combination treatment regimen for gastric cancer. Furthermore, the existence of caspase‐independent apoptotic pathway induced by treatment of ABT‐737 was not yet seen until combined with DMC, which shed light on an alternative mechanism involved in Bcl‐2 inhibitor‐induced apoptosis.

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Section: Discussionsupporting

confidence: 92%

Dimethyl celecoxib sensitizes gastric cancer cells to ABT‐737 via AIF nuclear translocation

Zhang

Yan

et al. 2016

J Cellular Molecular Medi

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“…The incorporation of nitrogen on the most potent quinazolinone derivative has yielded two pyrimidinone analogs that have also exhibited potent inhibitory activity against mPGES‐1 in cell‐free, cellular, and whole blood assays. One of these pyrimidinone analogs have also displayed selectivity toward mPGES‐1 and efficacy in modulating PGE 2 synthesis in synovial fibroblasts and chondrocytes derived from rheumatoid arthritis or osteoarthritis patients . In addition, the dihydropyrimidinone scaffold was recognized by another research group to be a valuable tool for designing potent mPGES‐1 inhibitors …”

Section: Identification Of Novel Targets In the Arachidonic Acid Cascadementioning

confidence: 99%

“…The compensatory production of other prostanoids due to the inhibition of mPGES‐1 may be on the basis of such renal tolerability, as the levels of a PGI 2 metabolite (6‐keto‐PGF 1α ) were augmented in the urine of treated dogs . Indeed, cell‐based and in vivo studies have been demonstrating that mPGES‐1 inhibitors specifically inhibit PGE 2 generation, causing no alterations on the production of other prostanoids or shunting the pathway to the synthesis of other prostanoids . Indeed, the maintenance or increase of PGI 2 levels may be a safety mechanism of mPGES‐1 inhibitors, since this prostanoid exerts protective actions in the GI, CV and renal systems, which may circumvent the occurrence of adverse effects.…”

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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“…Another set of potent mPGES-1 inhibitors based on 2-aryl substituted quinazolin-4(3 H )-one, pyrido[4,3- d ]pyrimidin-4(3 H )-one, and pyrido[2,3- d ]pyrimidin-4(3 H )-one scaffolds were recently presented . The lead compounds blocked mPGES-1 activity in cell-free and A549 cellular assays at low nanomolar concentrations and showed good potency also in human whole blood assay (<400 nM).…”

Section: Structure–activity Relationships Of Mpges-1 Inhibitorsmentioning

confidence: 99%

“…The lead compounds blocked mPGES-1 activity in cell-free and A549 cellular assays at low nanomolar concentrations and showed good potency also in human whole blood assay (<400 nM). Lead compound 19 (GRC27864) was selective over other prostanoid synthases and effectively repressed PGE 2 synthesis in clinically relevant inflammatory settings …”

Section: Structure–activity Relationships Of Mpges-1 Inhibitorsmentioning

confidence: 99%

Design and Development of Microsomal Prostaglandin E₂ Synthase-1 Inhibitors: Challenges and Future Directions

Koeberle¹,

Laufer

Werz³

2016

J. Med. Chem.

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Microsomal prostaglandin E2 synthase (mPGES)-1 is responsible for the massive prostaglandin E2 (PGE2) formation during inflammation. Increasing evidence reveals mPGES-1 inhibitors as a safe alternative to nonsteroidal anti-inflammatory drugs. The first selective mPGES-1 inhibitors recently entered clinical trials. Major challenges for drug development have been the high plasma protein binding of lead structures, interspecies discrepancies, nuisance inhibition, sophisticated enzyme assays, and limited structural information about the mPGES-1 inhibitor binding site. Since most of these drawbacks could be solved during the past few years, we are standing at the threshold of a new era of mPGES-1-targeting anti-inflammatory drugs. This perspective introduces mPGES-1 as a key player within the network of eicosanoid biosynthesis and summarizes our current understanding of its structure and mechanism. Moreover, we present high-throughput and in silico screening techniques and discuss the structure-activity relationship and pharmacological potential of major mPGES-1 inhibitor classes in light of recent insights from pharmacophore models and cocrystallization studies.

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Development of 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E2 synthase-1 inhibitors

Cited by 30 publications

References 30 publications

Dimethyl celecoxib sensitizes gastric cancer cells to ABT‐737 via AIF nuclear translocation

Dimethyl celecoxib sensitizes gastric cancer cells to ABT‐737 via AIF nuclear translocation

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Design and Development of Microsomal Prostaglandin E₂ Synthase-1 Inhibitors: Challenges and Future Directions

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Development of 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E2 synthase-1 inhibitors

Cited by 30 publications

References 30 publications

Dimethyl celecoxib sensitizes gastric cancer cells to ABT‐737 via AIF nuclear translocation

Dimethyl celecoxib sensitizes gastric cancer cells to ABT‐737 via AIF nuclear translocation

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

Design and Development of Microsomal Prostaglandin E2 Synthase-1 Inhibitors: Challenges and Future Directions

Contact Info

Product

Resources

About

Design and Development of Microsomal Prostaglandin E₂ Synthase-1 Inhibitors: Challenges and Future Directions