Searching for New NO-Donor Aspirin-like Molecules: A New Class of Nitrooxy-acyl Derivatives of Salicylic Acid

Lazzarato, Loretta; Donnola, Monica; Rolando, Barbara; Marini, Elisabetta; Cena, Clara; Coruzzi, Gabriella; Guaita, Elena; Morini, Giuseppina; Fruttero, Roberta; Gasco, Alberto; Biondi, Stefano; Ongini, Ennio

doi:10.1021/jm701104f

Cited by 32 publications

(32 citation statements)

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“…The aspirin 44 and ibuprofen 45 hybrid NO-donors exhibited effective anti-inflammatory activity with reduced or no GI toxicities (Figure 12). Other aspirin analogs with NO-donor properties that exhibit platelet aggregation properties and no GI side effects have been disclosed (130).…”

Section: No-nsaidsmentioning

confidence: 99%

Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond

Rao

Knaus²

2008

J Pharm Pharm Sci

575

372

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ABSTRACT. Purpose. NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors has provided an enthralling evolution. Efforts to discover an ultimate magic bullet to treat inflammation continues to be an important drug design challenge. This review traces the origins of NSAIDs, their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects. Methods. Literature data is presented describing important discoveries pertaining to the sequential development of classical NSAIDs and then selective COX-2 inhibitors, their mechanism of action, the structural basis for COX inhibition, and recent discoveries. Results. A brief history of the development of NSAIDs and the market withdrawal of selective COX-2 inhibitors is explained, followed by the description of prostaglandin biosynthesis, COX isoforms, structure and function. The structural basis for COX-1 and COX-2 inhibition is described along with methods used to evaluate COX-1/COX-2 inhibition. This is followed by a section that encompasses the major chemical classes of selective COX-2 inhibitors. The final section describes briefly some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. Conclusions. A great deal of progress has been made toward developing novel anti-inflammatory agents. In spite of the tremendous advances in the last decade, the design and development of a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge.

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Section: No-nsaidsmentioning

confidence: 99%

Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond

Rao

Knaus²

2008

J Pharm Pharm Sci

575

372

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“…18 Aliquots of platelets (200 L at 108 cells mL -1 ) were incubated with inhibitors at different concentrations (diluted from 400-fold concentrated solutions in DMSO)…”

Section: Cox-1 Inhibitionmentioning

confidence: 99%

“…18 The monocytes (106 cells mL -1 were incubated with LPS (10 g mL -1 ) for 18 h at 37 °C in a 5% CO 2 atmosphere. Aliquots of LPSstimulated monocytes were centrifuged (300g, 8 min) and resuspended in fresh FCS-free RPMI-1640 medium.…”

Section: Cox-2 Inhibitionmentioning

confidence: 99%

“…1B). 18 In order to explore the influence exerted by the nature of the NO-donor moiety on the pharmacological profile of this new type of products, we here describe the synthesis and pharmacological activity of a new class of compounds, obtained by substituting acyl groups containing NO-donor furoxan moieties for acetyl group of ASA (compounds 13, 14, 17 and 18, Fig. 2).…”

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confidence: 99%

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Searching for new NO-donor aspirin-like molecules: Furoxanylacyl derivatives of salicylic acid and related furazans

Lazzarato

Cena

Rolando

et al. 2011

Bioorganic & Medicinal Chemistry

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A new group of derivatives of salicylic acid containing NO-donor furoxans, and the related des-NO-furazans, were synthesized and evaluated as new aspirin-like molecules. Their stability was assessed in acid (pH 1) and physiological solutions (pH 7.4), and in human serum. No compound exhibited COX-inhibitory activity against COX-1 and COX-2 isoforms, when tested up to 100 lM, respectively, on isolated platelets and on monocytes. Phenylsulfonyl-and cyano-substituted furoxans inhibited platelet aggregation induced by collagen in human platelet-rich plasma, through a cGMP dependent mechanism. Furoxan derivatives displayed cGMP-dependent vasodilator activities, tested on rat aorta strips precontracted with phenylephrine. All products showed antiinflammatory activity similar to that of ASA, tested on rats by the carrageenan-induced paw edema assay. Unlike ASA, all products showed markedly reduced gastrotoxicity in a rat lesion model. IntroductionThe major limitation on the prolonged use of aspirin (ASA) 1 (Fig. 1) is its gastrotoxicity, responsible for gastric ulceration, exacerbation of peptic ulcer symptoms, gastrointestinal hemorrhage, erosive gastritis, delay in ulcer healing and, in some cases, death. 1-3This is a prominent problem, in view of the widespread use of ASA to treat headache, rheumatic pain and inflammation, as well as for its effective antithrombotic activity. 1,4,5 A number of new therapeutic perspectives are emerging for this enigmatic and intriguing drug, including its ability to reduce the risk of colorectal adenoma or cancer, and that of the recurrence of colorectal adenoma in high risk patients. [6][7][8] The beneficial pharmacological actions of ASA are predominantly dependent on its ability to inhibit both isoforms of the COX-enzyme, with a preference for the COX-1 isoform, with consequent inhibition of prostanoid production. 9 Unlike the other nonsteroidal antiinflammatory drugs (NSAIDs), ASA irreversibly inhibits both COX-1 and COX-2, by forming a covalent bond with the serine residue (Ser530) positioned in the arachidonic acid-binding channel of the enzymes. COX-1 is prevalently a constitutive enzyme, present in many tissues and cells, including platelets, and it is thought to be largely responsible for the antithrombotic effect of ASA.By contrast, inhibition of the COX-2 enzyme, prevalently an inducible isoform expressed by inflammatory stimuli in many tissues, is largely responsible for the drug's anti-inflammatory, analgesic, and antiproliferative actions. 9 ASA's gastrotoxicity involves local and systemic mechanisms. 1,10,11 Local mechanisms include interaction with phospholipids, weakening of the hydrophobic surface barrier in membranes, and the diffusion and subsequent entrapment of the drug into the mucosal cell, with consequent trapping of hydrogen ions, or both. These events principally depend on the product's pKa and lipophilicity. The systemic mechanisms are mainly related to the drug's ability to inhibit the COX-1 enzyme present in gastric epithelial cells, and conseque...

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“…Particularly relevant will be the use of hybrid drugs, such as the modified nonsteroidal anti-inflammatory drugs (NSAIDs), currently under development [28].…”

Section: What Is To Comementioning

confidence: 99%

Endothelial dysfunction in type 2 diabetes

Natali

Ferrannini

2012

Diabetologia

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The mechanisms responsible for the accelerated atherosclerosis observed in type 2 diabetes are not fully understood. One of the earliest events in the development of atherosclerosis is endothelial dysfunction, namely, a reduction in nitric oxide (NO) synthesis or its bioavailability within the peri-endothelial environment, where it is responsible for maintenance of vascular tissue integrity. The clinical evaluation of this pathway is hampered by the fact that in vivo NO cannot be directly measured; however, exploiting a novel, complex and elegant experimental setup, McVeigh and co-workers (Diabetologia 1992;35:771-776) were the first to document that NO bioavailability in type 2 diabetic patients is indeed reduced. In this edition of 'Then and now' that paper is reappraised not only for its originality, but also for the broad and extensive evaluation of the vascular functions explored, the complete clinical characterisation of patients enrolled and for the fact that all the major findings were subsequently replicated.

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Searching for New NO-Donor Aspirin-like Molecules: A New Class of Nitrooxy-acyl Derivatives of Salicylic Acid

Cited by 32 publications

References 50 publications

Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond

Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond

Searching for new NO-donor aspirin-like molecules: Furoxanylacyl derivatives of salicylic acid and related furazans

Endothelial dysfunction in type 2 diabetes

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