Thromboxane synthetase inhibitors (TXSI). Design, synthesis, and evaluation of a novel series of .omega.-pyridylalkenoic acids

Kato, Keita; Ohkawa, Shigenori; Terao, Shinji; Terashita, Zen‐ichi; Nishikawa, Kohei

doi:10.1021/jm00381a005

Cited by 109 publications

(67 citation statements)

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“…Licofelone, bovine insulin, and anti-6-keto PGF 1␣ antibody were generous gifts by Merckle GmbH (Ulm, Germany), Sanofi-Aventis (Frankfurt, Germany), and Dr. T. Dingermann (University of Frankfurt, Frankfurt, Germany), respectively. The thromboxane synthase inhibitor CV4151 was synthesized according to Kato et al (1985). Other materials and their sources are as follows: DMEM/high-glucose (4.5 g/l) medium, penicillin, streptomycin, trypsin/EDTA solution (PAA Laboratories GmbH, Coelbe, Germany); PGH 2 (Larodan, Malmö, Sweden); 11␤-PGE 2 , PGB 1 , MK-886, 6-keto PGF 1␣ , human recombinant COX-2, ovine-isolated COX-1 (Cayman Chemical, Ann Arbor, MI); [5,6,8,9,11,12,14,15-3 H]arachidonic acid ([ 3 H]arachidonic acid) (BioTrend Chemicals GmbH, Cologne, Germany); and Ultima Gold XR (PerkinElmer Life and Analytical Sciences, Boston, MA).…”

Section: Methodsmentioning

confidence: 99%

Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1

Koeberle

Siemoneit²,

Bühring³

et al. 2008

J Pharmacol Exp Ther

153

237

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The anti-inflammatory drug licofelone [ϭML3000; 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid], currently undergoing phase III trials for osteoarthritis, inhibits the prostaglandin (PG) and leukotriene biosynthetic pathway. Licofelone was reported to suppress the formation of PGE 2 in various cell-based test systems, but the underlying molecular mechanisms are not entirely clear. Here, we examined the direct interference of licofelone with enzymes participating in PGE 2 biosynthesis, that is, cyclooxygenase (COX)-1 and COX-2 as well as microsomal PGE 2 synthase (mPGES)-1. Licofelone concentration-dependently inhibited isolated COX-1 (IC 50 ϭ 0.8 M), whereas isolated COX-2 was less affected (IC 50 Ͼ 30 M). However, licofelone efficiently blocked the conversion of PGH 2 to PGE 2 mediated by mPGES-1 (IC 50 ϭ 6 M) derived from microsomes of interleukin-1␤-treated A549 cells, being about equipotent to 3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK-886), a well recognized mPGES-1 inhibitor. In intact interleukin-1␤-treated A549 cells, licofelone potently (IC 50 Ͻ 1 M) blocked formation of PGE 2 in response to calcimycin (A23187) plus exogenous arachidonic acid, but the concomitant generation of 6-keto PGF 1␣ , used as a biomarker for COX-2 activity, was not inhibited. We conclude that licofelone suppresses inflammatory PGE 2 formation preferentially by inhibiting mPGES-1 at concentrations that do not affect COX-2, implying an attractive and thus far unique molecular pharmacological dynamics as inhibitor of COX-1, the 5-lipoxygenase pathway, and of mPGES-1.Prostaglandins (PGs) and leukotrienes are powerful bioactive lipid mediators that are involved not only in numerous homeostatic biological functions but also in inflammation (Funk, 2001). The biosynthesis of PGs is initialized by COX isoenzymes, namely, COX-1, a constitutively expressed enzyme in numerous cell types thought to provide PGs mainly for physiological functions; and COX-2, an inducible isoform in inflammatory cells, primarily producing PGs relevant for inflammation, fever, and pain (Hawkey, 1999). After conversion of arachidonic acid to PGH 2 by COX enzymes, PGH 2 is subsequently isomerized by three different PGE 2 synthases to PGE 2 . Whereas the cytosolic PGE 2 synthase (cPGES) and the membrane-bound PGE 2 synthase (mPGES)-2 are constitutive enzymes, the mPGES-1 is an inducible isoform (Samuelsson et al., 2007). Cotransfection experiments of COX-1/2 with PGES isoenzymes imply that select molecular interactions between COX and PGES isoenzymes cause preferential functional coupling (Murakami et al., 2000;Samuelsson et al., 2007). Thus, cPGES uses PGH 2 produced by COX-1, whereas mPGES-1 receives PGH 2 from COX-2. PGE 2 plays a major role in the pathophysiology of inflammation, pain, and pyresis, but it also regulates physiological functions in the gastrointestinal tract, the kidney, and in the immune and nervous system (Smith, 1989). The nonsteroidal anti-inflamm...

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Section: Methodsmentioning

confidence: 99%

Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1

Koeberle

Siemoneit²,

Bühring³

et al. 2008

J Pharmacol Exp Ther

153

237

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“…The thromboxane synthase inhibitor CV4151 [22] and anti-6-keto PGF 1α antibody were generous gifts by Dr. S. Laufer (University of Tuebingen, Germany) and Dr. T. Dingermann (University of Frankfurt, Germany), respectively. Materials used: DMEM/High Glucose (4.5 g/l) medium, penicillin, streptomycin, trypsin/EDTA solution, PAA (Coelbe, Germany); Ultima Gold TM XR, Perkin Elmer (Boston, MA).…”

Section: Reagentsmentioning

confidence: 99%

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Koeberle

Northoff

Werz

2009

Biochemical Pharmacology

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To cite this version:Andreas Koeberle, Hinnak Northoff, Oliver Werz. Identification of 5-lipoxygenase and microsomal prostaglandin E synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol. Biochemical Pharmacology, Elsevier, 2009, 77 (9) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Ca 2+ -ionophore (A23187)-induced arachidonic acid release in neutrophils nor COX-2 activity in A549 cells or whole blood, measured as formation of 6-keto PGF 1α , or isolated human recombinant COX-2 were significantly affected by garcinol (≤ 30 µM). Together, the high potency of garcinol to selectively suppress PGE 2 synthesis and 5-lipoxygenase product formation provides a molecular basis for the anti-inflammatory and anti-carcinogenic effects of garcinol and rationalizes its therapeutic use.

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“…The alkene moiety was favorable for activity, because reduction of the ethylenic bond in 7 resulted in decreased activity (11).…”

Section: Biological Activitymentioning

confidence: 99%

Synthesis and Precocious Metamorphosis-Inducing Activity of 3-(1-Alkenyl) pyridines

Yoshida

Shiotsuki²,

Kuwano

2000

J. Pestic. Sci.

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A series of 3-pyridine derivatives with an 1-alkenyl group was synthesized and evaluated against 4th instar (penultimate) larvae of the silkworm, Bombyx mori, for their activity to induce precocious metamorphosis.Of the compounds tested, 3-(2-methyl-l-phenyl-l-propenyl)pyridine (18) was the most active, indicating that both a phenyl substituent at the 1 position and a short alkyl chain at the 2 position in the ethenyl moiety were significant for activity. Precocious pupation induced by 18 was accompanied by the prolongation of the larval period and the increase of body weights. Both 20-hydroxyecdysone and methoprene, a juvenile hormone agonist, could fully counteract precocious metamorphosis induced by 18. When applied to newly molted 4th instar larvae, 18 suppressed the increase of hemolymph ecdysteroid titers leading to larval ecdysis to 5th instar. These results indicated that 18 acted as an anti-ecdysteroid agent and temporarily depressed the ecdysteroid titer in the hemolymph to induce precocious metamorphosis.

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Thromboxane synthetase inhibitors (TXSI). Design, synthesis, and evaluation of a novel series of .omega.-pyridylalkenoic acids

Cited by 109 publications

References 0 publications

Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1

Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Synthesis and Precocious Metamorphosis-Inducing Activity of 3-(1-Alkenyl) pyridines

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Thromboxane synthetase inhibitors (TXSI). Design, synthesis, and evaluation of a novel series of .omega.-pyridylalkenoic acids

Cited by 109 publications

References 0 publications

Licofelone Suppresses Prostaglandin E2 Formation by Interference with the Inducible Microsomal Prostaglandin E2 Synthase-1

Licofelone Suppresses Prostaglandin E2 Formation by Interference with the Inducible Microsomal Prostaglandin E2 Synthase-1

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Synthesis and Precocious Metamorphosis-Inducing Activity of 3-(1-Alkenyl) pyridines

Contact Info

Product

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Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1

Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1