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  1. Article: Synthesis and anti-inflammatory activity of a series of N-substituted naproxen glycolamides: nitric oxide-donor naproxen prodrugs.

    Ranatunge, Ramani R / Augustyniak, Michael E / Dhawan, Vijay / Ellis, James L / Garvey, David S / Janero, David R / Letts, L Gordon / Richardson, Stewart K / Shumway, Mathew J / Trocha, A Mark / Young, Delano V / Zemtseva, Irina S

    Bioorganic & medicinal chemistry

    2006  Volume 14, Issue 8, Page(s) 2589–2599

    Abstract: A series of glycolamide naproxen prodrugs containing a nitrate group as a nitric oxide (NO) donor moiety has been synthesized. These compounds were evaluated for their anti-inflammatory activity, naproxen release, and gastric tolerance. Compounds 4a, 4b, ...

    Abstract A series of glycolamide naproxen prodrugs containing a nitrate group as a nitric oxide (NO) donor moiety has been synthesized. These compounds were evaluated for their anti-inflammatory activity, naproxen release, and gastric tolerance. Compounds 4a, 4b, 5a, 5b, 7b, and 7c exhibited anti-inflammatory activity equivalent to that of the parent NSAID, naproxen-Na, in the rat carrageenan paw edema model. At equimolar doses relative to naproxen-Na, the NO-donor glycolamide derivatives 4a, 4b, 5a, 5b, 7b, and 7c were gastro-sparing in the rat. Naproxen formation from these NO-donor glycolamides varied among the structures examined, with the N-substituent on the amide group having a particular influence, and demonstrated their prodrug nature. Compound 7b was selected for exemplary demonstration that the glycolamide nitrates can be bioactivated to release NO. These data open the possibility that naproxen glycolamide nitrates may represent a safer alternative to naproxen as anti-inflammatory medicines.
    MeSH term(s) Amides/chemistry ; Animals ; Anti-Inflammatory Agents/chemical synthesis ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Gastritis/chemically induced ; Humans ; Magnetic Resonance Spectroscopy ; Male ; Mass Spectrometry ; Naproxen/chemical synthesis ; Naproxen/chemistry ; Naproxen/pharmacology ; Nitric Oxide Donors/chemical synthesis ; Nitric Oxide Donors/chemistry ; Nitric Oxide Donors/pharmacology ; Prodrugs ; Rats ; Rats, Sprague-Dawley
    Chemical Substances Amides ; Anti-Inflammatory Agents ; Nitric Oxide Donors ; Prodrugs ; Naproxen (57Y76R9ATQ)
    Language English
    Publishing date 2006-04-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 1161284-8
    ISSN 1464-3391 ; 0968-0896
    ISSN (online) 1464-3391
    ISSN 0968-0896
    DOI 10.1016/j.bmc.2005.11.040
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3815: Show issues Location:
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  2. Article: 3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone as a potent and orally active cyclooxygenase-2 selective inhibitor: synthesis and biological evaluation.

    Khanapure, Subhash P / Augustyniak, Michael E / Earl, Richard A / Garvey, David S / Letts, L Gordon / Martino, Allison M / Murty, Madhavi G / Schwalb, David J / Shumway, Matthew J / Trocha, Andrzej M / Young, Delano V / Zemtseva, Irina S / Janero, David R

    Journal of medicinal chemistry

    2005  Volume 48, Issue 11, Page(s) 3930–3934

    Abstract: Incorporation of a spacer group between the central scaffold and the aryl ring resulted in a new cyclooxygenase-2 (COX-2) selective inhibitor core structure, 3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone (20), with COX-2 IC50 = ...

    Abstract Incorporation of a spacer group between the central scaffold and the aryl ring resulted in a new cyclooxygenase-2 (COX-2) selective inhibitor core structure, 3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone (20), with COX-2 IC50 = 0.25 microM and COX-1 IC50 = 14 microM (human whole blood assay). Compound 20 was orally active in the rat air pouch model of inflammation, inhibiting white blood cell infiltration and COX-2-derived PG production. Our data support the identification of a novel COX-2 selective inhibitor core structure exemplified by 20.
    MeSH term(s) Administration, Oral ; Animals ; Carrageenan ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/chemical synthesis ; Cyclooxygenase Inhibitors/chemistry ; Cyclooxygenase Inhibitors/pharmacology ; Dinoprostone/antagonists & inhibitors ; Dinoprostone/biosynthesis ; Inflammation/chemically induced ; Inflammation/metabolism ; Male ; Prostaglandin-Endoperoxide Synthases/metabolism ; Pyridines/chemical synthesis ; Pyridines/chemistry ; Pyridines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Sulfones/chemical synthesis ; Sulfones/chemistry ; Sulfones/pharmacology
    Chemical Substances 3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl) phenyl ketone ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors ; Pyridines ; Sulfones ; Carrageenan (9000-07-1) ; Cyclooxygenase 2 (EC 1.14.99.1) ; Prostaglandin-Endoperoxide Synthases (EC 1.14.99.1) ; Dinoprostone (K7Q1JQR04M)
    Language English
    Publishing date 2005-06-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm0582064
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Structure-based design, synthesis, and biological evaluation of indomethacin derivatives as cyclooxygenase-2 inhibiting nitric oxide donors.

    Wey, Shiow-Jyi / Augustyniak, Michael E / Cochran, Edward D / Ellis, James L / Fang, Xinqin / Garvey, David S / Janero, David R / Letts, L Gordon / Martino, Allison M / Melim, Terry L / Murty, Madhavi G / Richardson, Steward K / Schroeder, Joseph D / Selig, William M / Trocha, A Mark / Wexler, Roseanne S / Young, Delano V / Zemtseva, Irina S / Zifcak, Brian M

    Journal of medicinal chemistry

    2007  Volume 50, Issue 25, Page(s) 6367–6382

    Abstract: Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a ... ...

    Abstract Indomethacin, a nonselective cyclooxygenase (COX) inhibitor, was modified in three distinct regions in an attempt both to increase cyclooxygenase-2 (COX-2) selectivity and to enhance drug safety by covalent attachment of an organic nitrate moiety as a nitric oxide donor. A human whole-blood COX assay shows the modifications on the 3-acetic acid part of the indomethacin yielding an amide-nitrate derivative 32 and a sulfonamide-nitrate derivative 61 conferred COX-2 selectivity. Along with their respective des-nitrate analogs, for example, 31 and 62, the nitrates 32 and 61 were effective antiinflammatory agents in the rat air-pouch model. After oral dosing, though, only 32 increased nitrate and nitrite levels in rat plasma, indicating that its nitrate tether served as a nitric oxide donor in vivo. In a rat gastric injury model, examples 31 and 32 both show a 98% reduction in gastric lesion score compared to that of indomethacin. In addition, the nitrated derivative 32 inducing 85% fewer gastric lesions when coadministered with aspirin as compared to the combination of aspirin and valdecoxib.
    MeSH term(s) Animals ; Aspirin/adverse effects ; Celecoxib ; Cyclooxygenase 2 Inhibitors/adverse effects ; Cyclooxygenase 2 Inhibitors/chemical synthesis ; Cyclooxygenase 2 Inhibitors/pharmacology ; Drug Design ; Drug Synergism ; Female ; Gastric Mucosa/pathology ; Humans ; Hydroxamic Acids/adverse effects ; Hydroxamic Acids/chemical synthesis ; Hydroxamic Acids/pharmacology ; Indomethacin/adverse effects ; Indomethacin/analogs & derivatives ; Indomethacin/chemical synthesis ; Indomethacin/pharmacology ; Male ; Nitric Oxide Donors/adverse effects ; Nitric Oxide Donors/chemical synthesis ; Nitric Oxide Donors/pharmacology ; Pyrazoles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Stomach Ulcer/chemically induced ; Stomach Ulcer/pathology ; Structure-Activity Relationship ; Sulfonamides/pharmacology
    Chemical Substances Cyclooxygenase 2 Inhibitors ; Hydroxamic Acids ; Nitric Oxide Donors ; Pyrazoles ; Sulfonamides ; Celecoxib (JCX84Q7J1L) ; Aspirin (R16CO5Y76E) ; Indomethacin (XXE1CET956)
    Language English
    Publishing date 2007-12-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm0611861
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: NMI-1182, a gastro-protective cyclo-oxygenase-inhibiting nitric oxide donor.

    Ellis, James L / Augustyniak, Michael E / Cochran, Edward D / Earl, Richard A / Garvey, David S / Gordon, Laura J / Janero, David R / Khanapure, Subhash P / Letts, L Gordon / Melim, Terry L / Murty, Madhavi G / Schwalb, David J / Shumway, Matthew J / Selig, William M / Trocha, A Mark / Young, Delano V / Zemtseva, Irina S

    Inflammopharmacology

    2005  Volume 12, Issue 5-6, Page(s) 521–534

    Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and to provide pain relief but suffer from a major liability concerning their propensity to cause gastric damage. As nitric oxide (NO) is known to be gastro-protective ... ...

    Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat inflammation and to provide pain relief but suffer from a major liability concerning their propensity to cause gastric damage. As nitric oxide (NO) is known to be gastro-protective we have synthesized a NO-donating prodrug of naproxen named NMI-1182. We evaluated two cyclo-oxygenase (COX)-inhibiting nitric oxide donors (CINODs), NMI-1182 and AZD3582, for their ability to be gastro-protective compared to naproxen and for their anti-inflammatory activity. NMI-1182 and AZD3582 were found to produce similar inhibition of COX activity to that produced by naproxen. Both NMI-1182 and AZD3582 produced significantly less gastric lesions after oral administration than naproxen. All three compounds effectively inhibited paw swelling in the rat carrageenan paw edema model. In the carrageenan air pouch model all three compounds significantly reduced PGE2 levels in the pouch exudate but only NMI-1182 and naproxen inhibited leukocyte influx. These data demonstrate that NMI-1182 has comparable anti-inflammatory activity to naproxen but with a much reduced likelihood to cause gastric damage.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/blood ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Aorta, Abdominal/drug effects ; Aorta, Abdominal/physiology ; Carrageenan ; Cyclooxygenase 1/blood ; Cyclooxygenase 2/blood ; Cyclooxygenase Inhibitors/blood ; Cyclooxygenase Inhibitors/chemistry ; Cyclooxygenase Inhibitors/pharmacology ; Dinoprostone/antagonists & inhibitors ; Dinoprostone/metabolism ; Dose-Response Relationship, Drug ; Edema/chemically induced ; Edema/prevention & control ; Gastric Mucosa/drug effects ; Gastric Mucosa/metabolism ; Gastric Mucosa/pathology ; Humans ; In Vitro Techniques ; Inflammation/chemically induced ; Inflammation/prevention & control ; Male ; Molecular Structure ; Naphthalenes/blood ; Naphthalenes/chemistry ; Naphthalenes/pharmacology ; Naproxen/blood ; Naproxen/chemistry ; Naproxen/pharmacology ; Neutrophil Infiltration/drug effects ; Nitric Oxide Donors/blood ; Nitric Oxide Donors/chemistry ; Nitric Oxide Donors/pharmacology ; Protective Agents/chemistry ; Protective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Vasodilation/drug effects
    Chemical Substances Anti-Inflammatory Agents ; Cyclooxygenase Inhibitors ; NMI-1182 ; Naphthalenes ; Nitric Oxide Donors ; Protective Agents ; des-NO-NMI-1182 ; naproxen-n-butyl nitrate ; Naproxen (57Y76R9ATQ) ; Carrageenan (9000-07-1) ; Cyclooxygenase 1 (EC 1.14.99.1) ; Cyclooxygenase 2 (EC 1.14.99.1) ; Dinoprostone (K7Q1JQR04M)
    Language English
    Publishing date 2005
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1080058-x
    ISSN 1568-5608 ; 0925-4692
    ISSN (online) 1568-5608
    ISSN 0925-4692
    DOI 10.1163/156856005774382661
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3274: Show issues Location:
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