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Article: Synthesis of the nakanishi ring-locked retinoid.

Côté, Jamie B / Quach, Tan D / Demenev, Andrey P / Garvey, David S / Berman, Judd M

International journal of medicinal chemistry

2011 Volume 2011, Page(s) 826792

Abstract: An optimized synthetic route to prepare ring-locked retinoid 1a has been developed. We fully describe a purification protocol that provides isomerically pure 1a in support of on-going proof of concept studies for the development of therapeutic agents to ... ...

Abstract	An optimized synthetic route to prepare ring-locked retinoid 1a has been developed. We fully describe a purification protocol that provides isomerically pure 1a in support of on-going proof of concept studies for the development of therapeutic agents to treat human ADRP. Additionally, we have found that isomerically pure 1a can be stored in amber vials under argon at -20°C for use over time (up to six months) without degradation. Thus, enabling 1a to be an accessible and valuable biological tool.
Language	English
Publishing date	2011-10-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2582356-5
ISSN	2090-2077 ; 2090-2069
ISSN (online)	2090-2077
ISSN	2090-2069
DOI	10.1155/2011/826792
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers.

Khanapure, Subhash P / Garvey, David S / Janero, David R / Letts, L Gordon

Current topics in medicinal chemistry

2007 Volume 7, Issue 3, Page(s) 311–340

Abstract: In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2 and the release of arachidonic acid (AA) from membrane phospholipids. The AA is subsequently transformed by cyclooxygenase (COX) and lipoxygenase (LO) ... ...

Abstract	In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2 and the release of arachidonic acid (AA) from membrane phospholipids. The AA is subsequently transformed by cyclooxygenase (COX) and lipoxygenase (LO) pathways to prostaglandins, thromboxane and leukotrienes collectively termed eicosanoids. Eicosanoid production is considerably increased during inflammation. Both COX and LO pathways are of particular clinical relevance. The COX pathway is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), the most popular medications used to treat pain, fever and inflammation. Although their anti-inflammatory effects are well known, their long-term use is associated with gastrointestinal (GI) complications such as ulceration. In 1991, it was discovered that COX exists in two distinct isozymes, COX-1 and COX-2, of which COX-2 is primarily expressed at sites of inflammation and produces pro-inflammatory eicosanoids. For this reason, COX-2 selective inhibitors (COXIBs) have been developed recently as anti-inflammatory agents to minimize the risk of GI toxicity. Recently, some COX-2 selective inhibitors have shown adverse cardiovascular side effects, resulting in the withdrawal of rofecoxib and valdecoxib from the market. Selective inhibition of COX-2 without reducing COX-1-mediated thromboxane production could alter the balance between prostacyclin and thromboxane and promote a prothrombotic state, thereby explaining the observed COX-2 cardiovascular risk. In this review, we describe mechanisms for the production of pro-inflammatory eicosanoid mediators contributing to inflammation and summarize promising options for the prevention of inflammatory mediator formation and the therapeutic inhibition of pain and inflammation.
MeSH term(s)	Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Cyclooxygenase 2 Inhibitors/chemistry ; Cyclooxygenase 2 Inhibitors/pharmacology ; Cyclooxygenase 2 Inhibitors/therapeutic use ; Eicosanoids/biosynthesis ; Humans ; Inflammation/drug therapy ; Inflammation/metabolism ; Lipoxygenase/metabolism ; Prostaglandin-Endoperoxide Synthases/metabolism
Chemical Substances	Anti-Inflammatory Agents ; Cyclooxygenase 2 Inhibitors ; Eicosanoids ; Lipoxygenase (EC 1.13.11.12) ; Prostaglandin-Endoperoxide Synthases (EC 1.14.99.1)
Language	English
Publishing date	2007-02-16
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/156802607779941314
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Article: [No title information]

Fang, Xinqin / Bandarage, Upul K. / Wang, Tiansheng / Schroeder, Joseph D. / Garvey, David S.

Synlett

2003 Volume 2003, Issue 04

Abstract: The disulfide functionality exists in numerous organic compounds of interest in both chemistry and biology. In view of the fact that the disulfide function is highly susceptible to further oxidation by a broad range of agents, conducting a ... ...

Abstract	The disulfide functionality exists in numerous organic compounds of interest in both chemistry and biology. In view of the fact that the disulfide function is highly susceptible to further oxidation by a broad range of agents, conducting a chemoselective oxidation without further oxidizing the disulfide group poses a synthetic challenge. Disclosed herein are the first examples of such an oxidation in which a series of aldehyde disulfides (1A-E) were converted to the corresponding symmetrical carboxylic acid disulfides (2A-E), utilizing sodium chlorite as the oxidant, and dimethyl sulfoxide as both a reaction solvent and an efficient hypochlorous acid scavenger.
Keywords	aldehydes ; carboxylic Acids ; oxidation ; disulfides
Language	English
Publishing date	2003-02-26
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	2042012-2
ISSN	1437-2096 ; 0936-5214
ISSN (online)	1437-2096
ISSN	0936-5214
DOI	10.1055/s-2003-37518
Database	Thieme publisher's database

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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
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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
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Article: Synthesis and selective cyclooxygenase-2 (COX-2) inhibitory activity of a series of novel bicyclic pyrazoles.

Ranatunge, Ramani R / Garvey, David S / Janero, David R / Letts, L Gordon / Martino, Allison M / Murty, Madhavi G / Richardson, Stewart K / Young, Delano V / Zemetseva, Irina S

Bioorganic & medicinal chemistry

2004 Volume 12, Issue 6, Page(s) 1357–1366

Abstract: Novel series of pyrazolo[5,1-b]1,3-oxazolidines, pyrazolo[5,1-b]1,3-oxazines and imidazolidino[1,2-d]pyrazoles were synthesized. These compounds were evaluated in vitro for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in ...

Abstract	Novel series of pyrazolo[5,1-b]1,3-oxazolidines, pyrazolo[5,1-b]1,3-oxazines and imidazolidino[1,2-d]pyrazoles were synthesized. These compounds were evaluated in vitro for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in human whole blood (HWB). Several of the compounds were found to be novel and selective COX-2 inhibitors, the most potent and selective being 1-(5-cyclohexyl (2H,3H-pyrazolo[5,1-b]-1,3-oxazolidin-6-yl)-4-(methylsulfonyl)benzene, 7a (IC(5o) for COX-1>100 microM; for COX-2=1.3 microM).
MeSH term(s)	Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis ; Bridged Bicyclo Compounds, Heterocyclic/chemistry ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cyclooxygenase 1 ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/chemical synthesis ; Cyclooxygenase Inhibitors/chemistry ; Cyclooxygenase Inhibitors/pharmacology ; Humans ; Isoenzymes/antagonists & inhibitors ; Membrane Proteins ; Prostaglandin-Endoperoxide Synthases ; Pyrazoles/chemical synthesis ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Structure-Activity Relationship
Chemical Substances	Bridged Bicyclo Compounds, Heterocyclic ; 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	2004-03-15
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.2004.01.012
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Article: Combination of paclitaxel and nitric oxide as a novel treatment for the reduction of restenosis.

Lin, Chia-En / Garvey, David S / Janero, David R / Letts, L Gordon / Marek, Przemyslaw / Richardson, Stewart K / Serebryanik, Diana / Shumway, Matthew J / Tam, S William / Trocha, A Mark / Young, Delano V

Journal of medicinal chemistry

2004 Volume 47, Issue 9, Page(s) 2276–2282

Abstract: The combination of a nitric oxide (NO) donor and a paclitaxel-NO donor conjugate coated on a vascular stent was tested in a rabbit iliac artery model of stenosis as a potential therapy for restenosis. Paclitaxel was conjugated with a NO donor at the 7- ... ...

Abstract	The combination of a nitric oxide (NO) donor and a paclitaxel-NO donor conjugate coated on a vascular stent was tested in a rabbit iliac artery model of stenosis as a potential therapy for restenosis. Paclitaxel was conjugated with a NO donor at the 7-position to give compound 7. An adamantane-based NO donor 14 was synthesized and combined with 7 to provide a burst of NO in the first few critical hours following injury to the vessel wall. Both 7 and 14 demonstrated antiproliferative activity (IC(50) = 20 nM and 15 microM, respectively) and antiplatelet activity (IC(50) = 10 and 1 microM, respectively). Stents were coated with a layer of a polymer containing test compounds. The total amount of NO eluted from the stents after a 6 h implantation in the rabbit iliac artery was 35%, 95%, and 69% of the original content for the stents coated with 7, 14, and the combination of 7 and 14, respectively. The antistenotic activity of 7 and 14 was determined in a 28-day rabbit model with two control groups (uncoated stents and polymer-coated stents) and two study groups (paclitaxel-coated stents and stents coated with the combination of 7 and 14). Polymer-coated stents caused inflammation and increased stenosis by 39% when compared to the uncoated stents. The stents coated with 7 plus 14 were as good as the uncoated stents, 41% better than the polymer-coated stents and 34% better than the paclitaxel-coated stents. These data indicate a beneficial effect of adding NO to an antiproliferative agent (paclitaxel) and suggest a potential therapeutic combination for the treatment of stenotic vessel disease.
MeSH term(s)	Adamantane/analogs & derivatives ; Adamantane/chemical synthesis ; Adamantane/chemistry ; Adamantane/pharmacology ; Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Constriction, Pathologic/drug therapy ; Iliac Artery/drug effects ; Iliac Artery/pathology ; In Vitro Techniques ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/drug effects ; Nitric Oxide/metabolism ; Nitric Oxide Donors/chemical synthesis ; Nitric Oxide Donors/chemistry ; Nitric Oxide Donors/pharmacology ; Nitroso Compounds/chemical synthesis ; Nitroso Compounds/chemistry ; Nitroso Compounds/pharmacology ; Paclitaxel/analogs & derivatives ; Paclitaxel/chemical synthesis ; Paclitaxel/chemistry ; Paclitaxel/pharmacology ; Platelet Aggregation Inhibitors/chemical synthesis ; Platelet Aggregation Inhibitors/chemistry ; Platelet Aggregation Inhibitors/pharmacology ; Rabbits ; Recurrence ; Stents ; Vascular Diseases/drug therapy
Chemical Substances	7-(3-methyl-3-nitrosothiobutyryl)paclitaxel ; Antineoplastic Agents ; N,N-dimethyl-2-(2-(nitrosothio)adamantan-2-yl)acetamide ; Nitric Oxide Donors ; Nitroso Compounds ; Platelet Aggregation Inhibitors ; Nitric Oxide (31C4KY9ESH) ; Paclitaxel (P88XT4IS4D) ; Adamantane (PJY633525U)
Language	English
Publishing date	2004-04-22
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/jm0304111
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Article: A comparison of the cyclooxygenase inhibitor-NO donors (CINOD), NMI-1182 and AZD3582, using in vitro biochemical and pharmacological methods.

Young, Delano V / Cochran, Edward D / Dhawan, Vijay / Earl, Richard A / Ellis, James L / Garvey, David S / Janero, David R / Khanapure, Subhash P / Letts, L Gordon / Melim, Terry L / Murty, Madhavi G / Shumway, Matthew J / Wey, Shiow-Jyi / Zemtseva, Irina S / Selig, William M

Biochemical pharmacology

2005 Volume 70, Issue 9, Page(s) 1343–1351

Abstract: Cyclooxygenase (COX, EC 1.14.99.1) inhibitor-nitric oxide (NO) donor (CINOD) hybrid compounds represent an attractive alternative to NSAID and coxib therapy. This report compares two CINODs, NMI-1182 (naproxen-glyceryl dinitrate) and AZD3582 (naproxen-n- ... ...

Abstract	Cyclooxygenase (COX, EC 1.14.99.1) inhibitor-nitric oxide (NO) donor (CINOD) hybrid compounds represent an attractive alternative to NSAID and coxib therapy. This report compares two CINODs, NMI-1182 (naproxen-glyceryl dinitrate) and AZD3582 (naproxen-n-butyl nitrate), for their ability to inhibit COX-1 and -2, deliver bioavailable nitric oxide, and release naproxen, using in vitro biochemical and pharmacological methods. In human whole blood, both CINODs showed inhibition, comparable to naproxen, of both COX isozymes and slowly released naproxen. Both CINODs donated bioavailable NO, as detected by cGMP induction in the pig kidney transformed cell line, LLC-PK1, but NMI-1182 was more potent by 30-100 times than AZD3582, GTN, GDN, and ISDN and considerably faster in inducing cGMP synthesis than AZD3582. The nitrate groups of GTN, NMI-1182, and AZD3582 appeared to be bioactivated via a common pathway, since each compound desensitized LLC-PK1 cells to subsequent challenge with the other compounds. Similar cGMP induction also occurred in normal, untransformed cells (human renal proximal tubule epithelial cells and hepatocytes from man, rat, and monkey); again, NMI-1182 was superior to AZD3582. NMI-1182 was also the more metabolically labile compound, releasing more absolute nitrate and nitrite (total NO(x)) in human stomach (in which NO is salutary) and liver S9 homogenates. Naproxen was also more rapidly freed from NMI-1182 than AZD3582 in human stomach, although liver S9 hydrolyzed both CINODs with similar rates. These in vitro tests revealed that NMI-1182 may be a better CINOD than AZD3582 because of its superior NO donating and naproxen liberating properties.
MeSH term(s)	Cyclic GMP/biosynthesis ; Cyclooxygenase 1/drug effects ; Cyclooxygenase 2/drug effects ; Cyclooxygenase Inhibitors/pharmacology ; Humans ; Liver/metabolism ; Naphthalenes/pharmacokinetics ; Naphthalenes/pharmacology ; Naproxen/pharmacology ; Nitric Oxide/biosynthesis ; Nitric Oxide Donors/pharmacology
Chemical Substances	Cyclooxygenase Inhibitors ; NMI-1182 ; Naphthalenes ; Nitric Oxide Donors ; naproxen-n-butyl nitrate ; Nitric Oxide (31C4KY9ESH) ; Naproxen (57Y76R9ATQ) ; Cyclooxygenase 1 (EC 1.14.99.1) ; Cyclooxygenase 2 (EC 1.14.99.1) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2005-11-01
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2005.08.004
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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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Article: Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.

Ranatunge, Ramani R / Augustyniak, Michael / Bandarage, Upul K / Earl, Richard A / Ellis, James L / Garvey, David S / Janero, David R / Letts, L Gordon / Martino, Allison M / Murty, Madhavi G / Richardson, Stewart K / Schroeder, Joseph D / Shumway, Matthew J / Tam, S William / Trocha, A Mark / Young, Delano V

Journal of medicinal chemistry

2004 Volume 47, Issue 9, Page(s) 2180–2193

Abstract: The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ... ...

Abstract	The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
MeSH term(s)	Administration, Oral ; Animals ; Cyclooxygenase 1 ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/adverse effects ; Cyclooxygenase Inhibitors/chemical synthesis ; Cyclooxygenase Inhibitors/pharmacology ; Female ; Gastritis/chemically induced ; Humans ; In Vitro Techniques ; Isoenzymes/antagonists & inhibitors ; Male ; Membrane Proteins ; Nitrates/chemical synthesis ; Nitrates/chemistry ; Nitrates/pharmacology ; Nitric Oxide Donors/chemical synthesis ; Nitric Oxide Donors/chemistry ; Nitric Oxide Donors/pharmacology ; Prostaglandin-Endoperoxide Synthases ; Pyrazoles/chemical synthesis ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship
Chemical Substances	1-(1-cyclohexyl-3-(1-(hydroxyimino)-4-(nitrooxy)butyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors ; Isoenzymes ; Membrane Proteins ; Nitrates ; Nitric Oxide Donors ; 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) ; Ptgs1 protein, rat (EC 1.14.99.1)
Language	English
Publishing date	2004-04-22
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/jm030276s
Database	MEDical Literature Analysis and Retrieval System OnLINE

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