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  1. Article: Selective nitros(yl)ation induced in vivo by a nitric oxide-donating cyclooxygenase-2 inhibitor: a NObonomic analysis.

    Dhawan, Vijay / Schwalb, David J / Shumway, Matthew J / Warren, Michael C / Wexler, Roseanne S / Zemtseva, Irina S / Zifcak, Brian M / Janero, David R

    Free radical biology & medicine

    2005  Volume 39, Issue 9, Page(s) 1191–1207

    Abstract: Nitric oxide (NO) enhances anti-inflammatory drug action. Through a metabonomics approach termed "NObonomics," the effects of a prototypic NO donor (organic nitrate)-cyclooxygenase-2 inhibitor hybrid (NO-coxib), NMI-1093, on the NO metabolite status of ... ...

    Abstract Nitric oxide (NO) enhances anti-inflammatory drug action. Through a metabonomics approach termed "NObonomics," the effects of a prototypic NO donor (organic nitrate)-cyclooxygenase-2 inhibitor hybrid (NO-coxib), NMI-1093, on the NO metabolite status of the circulation and major organs have been profiled in vivo in the rat. An oral anti-inflammatory NMI-1093 bolus elicited acute tissue-, time-, and dose-dependent changes in oxidative and nitroso/nitrosyl NO metabolites. Gastric N-nitrosation and hepatic S-nitrosation and heme nitrosylation emerged as sensitive indices of this NO-coxib's metabolism. Acute NMI-1093-induced nitros(yl)ation correlated positively as a function of nitrate plus nitrite formation across all organs examined, suggesting a unifying in vivo mechanism consequent to NMI-1093 biotransformation that links oxidative and nitros(yl)ative routes of NO chemical biology and thereby may support downstream NO signaling. NMI-1093 depressed erythrocyte nitros(yl)ation, likely by inhibiting cellular carbonic anhydrase and shifting the intracellular balance between nitrogen oxides and carbonates. Glutathione-S-transferase or cytochrome P450 inhibitors also attenuated NMI-1093's NO metabolism in a compartment-selective fashion. Although not itself a NO donor, the des-nitro coxib analog of NMI-1093 influenced basal NO metabolite profiles, implicating a cyclooxygenase-NO synthase interaction in physiological NO regulation. By detailing the global NO metrics of a unique coxib bearing a popular NO-donor pharmacophore (i.e., a nitrate moiety) and defining some critical mechanistic determinants, this study demonstrates how NObonomics can serve as valuable tool in helping elucidate NO systems biology and the effect of NO-donor and non-NO-donating therapeutics thereon.
    MeSH term(s) Animals ; Brain/drug effects ; Brain/metabolism ; Carbonic Anhydrases/drug effects ; Cyclooxygenase 2 Inhibitors/administration & dosage ; Cyclooxygenase 2 Inhibitors/chemistry ; Cyclooxygenase 2 Inhibitors/pharmacology ; Dose-Response Relationship, Drug ; Erythrocytes/enzymology ; Heme/metabolism ; Kidney/drug effects ; Kidney/metabolism ; Liver/drug effects ; Liver/metabolism ; Male ; Nitrates/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Donors/administration & dosage ; Nitric Oxide Donors/chemistry ; Nitric Oxide Donors/pharmacology ; Nitrites/metabolism ; Oxazoles/administration & dosage ; Oxazoles/chemistry ; Oxazoles/pharmacology ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley ; Stomach/drug effects ; Stomach/metabolism ; Sulfonamides/administration & dosage ; Sulfonamides/chemistry ; Sulfonamides/pharmacology
    Chemical Substances Cyclooxygenase 2 Inhibitors ; NMI-1093 ; Nitrates ; Nitric Oxide Donors ; Nitrites ; OH-valdecoxib ; Oxazoles ; Sulfonamides ; Nitric Oxide (31C4KY9ESH) ; Heme (42VZT0U6YR) ; Carbonic Anhydrases (EC 4.2.1.1)
    Language English
    Publishing date 2005-11-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 807032-5
    ISSN 1873-4596 ; 0891-5849
    ISSN (online) 1873-4596
    ISSN 0891-5849
    DOI 10.1016/j.freeradbiomed.2005.06.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2109: Show issues Location:
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  2. Article: Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo.

    Janero, David R / Bryan, Nathan S / Saijo, Fumito / Dhawan, Vijay / Schwalb, David J / Warren, Michael C / Feelisch, Martin

    Proceedings of the National Academy of Sciences of the United States of America

    2004  Volume 101, Issue 48, Page(s) 16958–16963

    Abstract: Nitric oxide (NO)-derived products may modify tissue constituents, forming S- and N-nitroso adducts and metal nitrosyls implicated in NO signaling. Nitrovasodilator drugs have been in widespread use for more than a century, yet their biotransformation ... ...

    Abstract Nitric oxide (NO)-derived products may modify tissue constituents, forming S- and N-nitroso adducts and metal nitrosyls implicated in NO signaling. Nitrovasodilator drugs have been in widespread use for more than a century, yet their biotransformation pathways to NO and their effects as NO donors across tissues remain ill defined. By using a metabonomics approach (termed "NObonomics") for detailing the global NO-related metabolism of the cornerstone nitrovasodilator, glyceryl trinitrate (GTN; 0.1-100 mg/kg), in the rat in vivo, we find that GTN biotransformation elicits extensive tissue nitros(yl)ation throughout all major organ systems. The corresponding reaction products remained detectable hours after administration, and vascular tissue was not a major nitros(yl)ation site. Extensive heart and liver modifications involved both S- and N-nitrosation, and RBC S-nitrosothiol formation emerged as a sensitive indicator of organic nitrate metabolism. The dynamics of GTN-derived oxidative NO metabolites in blood did not reflect the nitros(yl)ation patterns in the circulation or in tissues, casting doubt on the usefulness of plasma nitrite/nitrate as an index of NO/NO-donor biodynamics. Target-tissue NO metabolites varied in amount and type with GTN dose, suggesting a dose-sensitive shift in the prevailing routes of GTN biotransformation ("metabolic shunting") from thiol nitrosation to heme nitrosylation. We further demonstrate that GTN-induced nitros(yl)ation is modulated by a complex, tissue-selective interplay of enzyme-catalyzed pathways. These findings provide insight into the global in vivo metabolism of GTN at pharmacologically relevant doses and offer an additional experimental paradigm for the NObonomic analysis of NO-donor metabolism and signaling.
    MeSH term(s) Animals ; Biotransformation ; Dose-Response Relationship, Drug ; Male ; Nitric Oxide/metabolism ; Nitric Oxide Donors/administration & dosage ; Nitroglycerin/blood ; Nitroglycerin/pharmacokinetics ; Rats ; Rats, Wistar
    Chemical Substances Nitric Oxide Donors ; Nitric Oxide (31C4KY9ESH) ; Nitroglycerin (G59M7S0WS3)
    Language English
    Publishing date 2004-11-30
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0406075101
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Natural products reveal cancer cell dependence on oxysterol-binding proteins.

    Burgett, Anthony W G / Poulsen, Thomas B / Wangkanont, Kittikhun / Anderson, D Ryan / Kikuchi, Chikako / Shimada, Kousei / Okubo, Shuichi / Fortner, Kevin C / Mimaki, Yoshihiro / Kuroda, Minpei / Murphy, Jason P / Schwalb, David J / Petrella, Eugene C / Cornella-Taracido, Ivan / Schirle, Markus / Tallarico, John A / Shair, Matthew D

    Nature chemical biology

    2011  Volume 7, Issue 9, Page(s) 639–647

    Abstract: Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. ...

    Abstract Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)--proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases.
    MeSH term(s) Biological Products/antagonists & inhibitors ; Biological Products/pharmacology ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cholestenones/antagonists & inhibitors ; Cholestenones/pharmacology ; Humans ; Hydroxycholesterols/pharmacology ; Lipid Metabolism/drug effects ; Neoplasms/metabolism ; Phenazines/antagonists & inhibitors ; Phenazines/pharmacology ; Receptors, Steroid/genetics ; Receptors, Steroid/metabolism ; Saponins/antagonists & inhibitors ; Saponins/pharmacology ; Signal Transduction/drug effects ; Sphingomyelins/biosynthesis ; Spiro Compounds/antagonists & inhibitors ; Spiro Compounds/pharmacology ; Steroids/antagonists & inhibitors ; Steroids/pharmacology ; Stilbenes/antagonists & inhibitors ; Stilbenes/pharmacology
    Chemical Substances Biological Products ; Carrier Proteins ; Cholestenones ; Hydroxycholesterols ; Phenazines ; Receptors, Steroid ; Saponins ; Sphingomyelins ; Spiro Compounds ; Steroids ; Stilbenes ; oxysterol binding protein ; ritterazine B ; schweinfurthin A ; cephalostatin I (112088-56-9) ; OSW 1 (145075-81-6) ; 25-hydroxycholesterol (767JTD2N31)
    Language English
    Publishing date 2011-08-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/nchembio.625
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: 3-(2-Methoxytetrahydrofuran-2-yl)pyrazoles: a novel class of potent, selective cyclooxygenase-2 (COX-2) inhibitors.

    Ranatunge, Ramani R / Earl, Richard A / Garvey, David S / Janero, David R / Letts, L Gordon / Martino, Allison M / Murty, Madhavi G / Richardson, Stewart K / Schwalb, David J / Young, Delano V / Zemtseva, Irina S

    Bioorganic & medicinal chemistry letters

    2004  Volume 14, Issue 24, Page(s) 6049–6052

    Abstract: A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4-10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4- ... ...

    Abstract A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4-10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4-methanesulfonylphenyl)-3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhibition (IC50 for COX-1: >100 microM and COX-2: 1.2 microM).
    MeSH term(s) Cyclooxygenase 1 ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/chemical synthesis ; Cyclooxygenase Inhibitors/chemistry ; Cyclooxygenase Inhibitors/pharmacology ; Drug Evaluation, Preclinical ; Humans ; Isoenzymes/antagonists & inhibitors ; Membrane Proteins ; Molecular Structure ; Prostaglandin-Endoperoxide Synthases/blood ; Prostaglandin-Endoperoxide Synthases/drug effects ; Pyrazoles/chemical synthesis ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Structure-Activity Relationship
    Chemical Substances Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors ; Isoenzymes ; Membrane Proteins ; Pyrazoles ; Cyclooxygenase 1 (EC 1.14.99.1) ; Cyclooxygenase 2 (EC 1.14.99.1) ; PTGS1 protein, human (EC 1.14.99.1) ; PTGS2 protein, human (EC 1.14.99.1) ; Prostaglandin-Endoperoxide Synthases (EC 1.14.99.1)
    Language English
    Publishing date 2004-12-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2004.09.073
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3203: Show issues Location:
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  5. 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
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  6. 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
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