L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3-methyl-5-propyl-4-benzofuranol): a novel, selective, orally active 5-lipoxygenase inhibitor

1987 ◽  
Vol 65 (12) ◽  
pp. 2441-2448 ◽  
Author(s):  
P. Belanger ◽  
A. Maycock ◽  
Y. Guindon ◽  
T. Bach ◽  
A. L. Dollob ◽  
...  
Keyword(s):  
Platelet Activating Factor ◽  
Human Leukocyte ◽  
Lipoxygenase Inhibitor ◽  
Lipoxygenase Inhibitors ◽  
Factor Ii ◽  
Mastocytoma Cells ◽  
Oral Activity ◽  
12 Lipoxygenase ◽  
Rat Paw ◽  
Orally Active

L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3-methyl-5-propyl-4-benzofuranol) was a potent inhibitor of leukotriene biosynthesis in intact rat and human leukocytes and CXBG mastocytoma cells (IC50 values, 18–240 nM) and of crude human leukocyte and highly purified porcine leukocyte 5-lipoxygenase (IC50 value, 4 × 10–7 M). The selectivity of L-656,224 for 5-lipoxygenase was shown through the relative lack of activity of the compound on 12-lipoxygenase, 15-lipoxygenase, cyclooxygenase, catalase, and myeloperoxidase. The compound showed (i) oral activity against hyperalgesia induced in the rat paw by injection of yeast or platelet-activating factor, (ii) dyspnea in sensitized inbred rats induced by an aerosol of antigen, and (iii) bronchoconstriction induced by an aerosol of Ascaris in squirrel monkeys, suggesting a role for 5-lipoxygenase inhibitors in the treatment of asthma and peripheral pain.

L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor

1989 ◽  
Vol 67 (5) ◽  
pp. 456-464 ◽  
Author(s):  
J. Gillard ◽  
A. W. Ford-Hutchinson ◽  
C. Chan ◽  
S. Charleson ◽  
D. Denis ◽  
...  
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Potent Inhibitor ◽  
Human Platelets ◽  
Ionophore A23187 ◽  
Lipoxygenase Inhibitor ◽  
12 Lipoxygenase ◽  
Rat Paw ◽  
Human Polymorphonuclear Leukocytes

L-663,536 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human polymorphonuclear leukocytes (PMN) (IC50, 2.5 nM). Similarly, L-663,536 inhibited A23187-induced LTB4 formation by rat peripheral blood and elicited PMN. At concentrations where inhibition of leukotriene biosynthesis occurred in human whole blood (1.1 μM), no effect was seen on cyclooxygenase or 12-lipoxygenase, an effect also observed in washed human platelets. The compound had no effect on rat or porcine 5-lipoxygenase indicating that L-663,536 is not a direct 5-lipoxygenase inhibitor. When administered in vivo L-663,536 was a potent inhibitor of antigen-induced dyspnea in inbred rats pretreated with methysergide (ED50, 0.036 mg/kg p.o.) and of Ascaris-induced bronchoconstriction in squirrel monkeys (1 mg/kg p.o.). The compound inhibited leukotriene biosynthesis in vivo in a rat pleurisy model (ED50, 0.2 mg/kg p.o.), an inflamed rat paw model (ED50, 0.8 mg/kg), a model of leukotriene excretion in rat bile following antigen provocation, and a model in the guinea-pig ear where leukotriene synthesis was induced by topical challenge with ionophore A23187 (ED50, 2.5 mg/kg p.o. and 0.6 μg topically). The results indicate that L-663,536 is a potent inhibitor of leukotriene biosynthesis both in vitro and in vivo indicating that the compound is suitable for studying the role of leukotrienes in a variety of pathological situations.Key words: leukotriene, 5-lipoxygenase, polymorphonuclear leukocytes, leukotriene B4, leukotriene inhibitor.

Studies on the roles of phospholipase A2 and eicosanoids in the regulation of corticotrophin secretion by rat pituitary cells in vitro

1991 ◽  
Vol 130 (1) ◽  
pp. 21-32 ◽  
Author(s):  
A. M. Cowell ◽  
R. J. Flower ◽  
J. C. Buckingham
Keyword(s):  
Arachidonic Acid ◽  
Platelet Activating Factor ◽  
Nordihydroguaiaretic Acid ◽  
Cyclooxygenase Inhibitors ◽  
Pituitary Cells ◽  
Lipoxygenase Inhibitor ◽  
Acth Secretion ◽  
Lipoxygenase Inhibitors ◽  
Prostaglandin F

ABSTRACT Dispersed anterior pituitary cells were used to investigate the possible roles of phospholipid metabolites released by phospholipase A2 (PLA2) in the control of immunoreactive ACTH (ir-ACTH) secretion in vitro. PLA2 (15 600–62 500 U/1), the PLA2 activator melittin (0·5–20 mg/l) and arachidonic acid (1 mmol/l) all produced increases in ir-ACTH release from the cells, whilst platelet-activating factor (PAF), prostaglandin F2α (PGF2α), the prostacyclin analogues iloprost and BW245C, the thromboxane A2 (TXA2) analogue U46619, and the leukotrienes LTB4 and LTC4 were ineffective in this respect. PGF2α (100 nmol/l and 1 μmol/l), iloprost (1 μmol/l) and BW245C (100 nmol/l and 1 μmol/l) depressed corticotrophin-releasing factor-41-induced ir-ACTH secretion, while the PAF antagonist BN52021 (10 and 100 μmol/l) and LTC4 (100 nmol/l and 1 μmol/l) had no discernable effects. The secretory responses of the cells to hypothalamic extracts (0·2 hypothalami/ml) and arachidonic acid (1 mmol/l) were generally unaffected by the cyclooxygenase inhibitors ibuprofen (10 and 100 μmol/l) and indomethacin (10 μmol/l), the TXA2 synthetase inhibitor imidazole (10 μmol/l–1 mmol/l), the lipoxygenase inhibitor nordihydroguaiaretic acid (10 and 100 μmol/l) and the dual cyclo-oxygenase/lipoxygenase inhibitors phenidone (1–100 μmol/l) and BW755C (10 and 100 μmol/l). They were, however, inhibited by the dual cyclo-oxygenase/lipoxygenase inhibitor eicosatetraynoic acid (10 and 100 μmol/l), which also blocks epoxygenase and PLA2 activity and by the cytochrome P450 inhibitor SKF-525A (1 mmol/l). The results suggest that the stimulatory effects of PLA2 and arachidonic acid on ir-ACTH secretion are not effected by products generated by the cyclo-oxygenase or lipoxygenase pathways but may be mediated by metabolites generated by the cytochrome P450 pathway. Journal of Endocrinology (1991) 130, 21–32

The effect of the orally active platelet-activating factor antagonist WEB 2086 in the treatment of asthma.

1994 ◽  
Vol 149 (5) ◽  
pp. 1142-1148 ◽  
Author(s):  
D P Spence ◽  
S L Johnston ◽  
P M Calverley ◽  
P Dhillon ◽  
C Higgins ◽  
...  
Keyword(s):  
Platelet Activating Factor ◽  
Orally Active ◽  
Factor Antagonist ◽  
Web 2086

Cmi-206: A potent dual platelet activating factor antagonist and 5-lipoxygenase inhibitor

1995 ◽  
Vol 5 (6) ◽  
pp. 643-648 ◽  
Author(s):  
Md. Sajjat Hussoin ◽  
Xiong Cai ◽  
Ralph T. Scannell ◽  
David Yaeger ◽  
David B. Killian ◽  
...  
Keyword(s):  
Platelet Activating Factor ◽  
Lipoxygenase Inhibitor ◽  
Factor Antagonist

scholarly journals Evaluation of Chemical Strategies for Improving the Stability and Oral Toxicity of Insecticidal Peptides

Biomedicines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 90 ◽  
Author(s):  
Volker Herzig ◽  
Aline de Araujo ◽  
Kathryn Greenwood ◽  
Yanni Chin ◽  
Monique Windley ◽  
...  
Keyword(s):  
Oral Toxicity ◽  
Peptide Backbone ◽  
Insect Midgut ◽  
Peptide Toxins ◽  
Oral Activity ◽  
The Stability ◽  
Reduced Rate ◽  
Chemical Strategies ◽  
Orally Active ◽  
Insecticidal Peptides

Spider venoms are a rich source of insecticidal peptide toxins. Their development as bioinsecticides has, however, been hampered due to concerns about potential lack of stability and oral bioactivity. We therefore systematically evaluated several synthetic strategies to increase the stability and oral potency of the potent insecticidal spider-venom peptide ω-HXTX-Hv1a (Hv1a). Selective chemical replacement of disulfide bridges with diselenide bonds and N- to C-terminal cyclization were anticipated to improve Hv1a resistance to proteolytic digestion, and thereby its activity when delivered orally. We found that native Hv1a is orally active in blowflies, but 91-fold less potent than when administered by injection. Introduction of a single diselenide bond had no effect on the susceptibility to scrambling or the oral activity of Hv1a. N- to C-terminal cyclization of the peptide backbone did not significantly improve the potency of Hv1a when injected into blowflies and it led to a significant decrease in oral activity. We show that this is likely due to a dramatically reduced rate of translocation of cyclic Hv1a across the insect midgut, highlighting the importance of testing bioavailability in addition to toxin stability.

scholarly journals Synthesis and Evaluation of New Coumarin Derivatives as Antioxidant, Antimicrobial, and Anti-Inflammatory Agents

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3251 ◽  
Author(s):  
Hanan M. Alshibl ◽  
Ebtehal S. Al-Abdullah ◽  
Mogedda E. Haiba ◽  
Hamad M. Alkahtani ◽  
Ghada E.A. Awad ◽  
...  
Keyword(s):  
Significant Inhibition ◽  
Coumarin Derivatives ◽  
Paw Oedema ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Rat Paw ◽  
Orally Active ◽  
Rat Paw Oedema ◽  
Sulfonamide Compound

New pyranocoumarin and coumarin-sulfonamide derivatives were prepared and evaluated for their antioxidant, antimicrobial, and/or anti-inflammatory activities. Coumarin-sulfonamide compounds 8a–d demonstrated significant antioxidant activity, while 7c,d, 8c,d, and 9c,d exhibited antimicrobial activity equal to or higher than the standard antimicrobials against at least one tested microorganism. Regarding the anti-inflammatory testing, pyranocoumarins 2b, 3a,b and 5c and coumarin-sulfonamide compound 9a showed more potent antiproteinase activity than aspirin in vitro; however, five compounds were as potent as aspirin. The anti-inflammatory activity of the promising compounds was further assessed pharmacologically on formaldehyde-induced rat paw oedema and showed significant inhibition of oedema. For in vitro COX-inhibitory activity of coumarin derivatives, pyranocoumarin derivative 5a was the most selective (SI = 152) and coumarin-sulfonamide derivative 8d was most active toward COX-2 isozyme. The most active derivatives met the in silico criteria for orally active drugs; thus, they may serve as promising candidates to develop more potent and highly efficient antioxidant, antimicrobial, and/or anti-inflammatory agents.

scholarly journals PAF-acether-induced release of tissue-type plasminogen activator from vessel walls

Blood ◽  
1985 ◽  
Vol 66 (1) ◽  
pp. 86-91 ◽  
Author(s):  
JJ Emeis ◽  
C Kluft
Keyword(s):  
Plasminogen Activator ◽  
Vascular Endothelial Cells ◽  
Platelet Activating Factor ◽  
Cyclooxygenase Inhibitors ◽  
Tissue Type ◽  
Lipoxygenase Pathway ◽  
Lipoxygenase Inhibitors ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

Abstract Platelet-activating factor (PAF-acether; 1–0-octadecyl-2-acetyl-sn- glyceryl-3-phosphorylcholine) induced the release of plasminogen activator in rat, both in vivo and in perfused hind legs. The released plasminogen activator was shown by immunologic and functional criteria to be tissue-type plasminogen activator (t-PA). Release of t-PA by PAF- acether could be inhibited by phospholipase inhibitors and by lipoxygenase inhibitors, but not by cyclooxygenase inhibitors. It is suggested that PAF-acether induces the release of t-PA from vascular endothelial cells by the (calcium-dependent) activation of a phospholipase-lipoxygenase pathway.

ChemInform Abstract: New Orally Active Serine Protease Inhibitors: Structural Requirements for Their Good Oral Activity.

ChemInform ◽  
2010 ◽  
Vol 27 (10) ◽  
pp. no-no
Author(s):  
K. SENOKUCHI ◽  
H. NAKAI ◽  
Y. NAKAYAMA ◽  
Y. ODAGAKI ◽  
K. SAKAKI ◽  
...  
Keyword(s):  
Serine Protease ◽  
Protease Inhibitors ◽  
Serine Protease Inhibitors ◽  
Structural Requirements ◽  
Oral Activity ◽  
Orally Active

scholarly journals Biosynthesis, structure and biological activity of hydroxyeicosatetraenoic acids in Hydra vulgaris

1993 ◽  
Vol 295 (1) ◽  
pp. 23-29 ◽  
Author(s):  
V Di Marzo ◽  
L De Petrocellis ◽  
C Gianfrani ◽  
G Cimino
Keyword(s):  
Nordihydroguaiaretic Acid ◽  
Hydra Vulgaris ◽  
Chiral Phase ◽  
Exogenous Fatty Acid ◽  
Bud Formation ◽  
Lipoxygenase Inhibitors ◽  
Almost All ◽  
12 Lipoxygenase ◽  
Hydroxyeicosatetraenoic Acids

Recent reports have suggested the involvement of arachidonic acid (AA) and its metabolites in the control of body pattern, head and tentacle regeneration and bud formation in Hydra spp. Here we describe for the first time the biosynthesis of hydroxyeicosatetraenoic acids (HETEs) in vitro by hydroid cytosolic extracts. Incubation of both unlabelled and tritiated AA with homogenates of Hydra vulgaris led to the conversion of up to 11% of the exogenous fatty acid into mainly two metabolites. These were characterized as 11-hydroperoxyeicosatetraenoic acid (11-HPETE) and 11-HETE by means of a combination of chromatographic, chemical, 1H-n.m.r. and electron-impact m.s. techniques. Trace amounts of 9-HETE and 12-HETE were also found. Analysis of 11-HETE by chiral-phase h.p.l.c. revealed that this metabolite was composed mainly of the R enantiomer. The production of 11-HPETE and 11-HETE was found to be: (1) associated with the cytosolic fraction of Hydra homogenates; (2) dependent on AA concentration, incubation time and protein amount in the homogenates; (3) unaffected by co-incubation with the 5- and 12-lipoxygenase inhibitors, 5,8,11-eicosatriynoic acid and nordihydroguaiaretic acid, the cyclo-oxygenase inhibitor, indomethacin, or the cytochrome P-450 inhibitors, proadifen and methoxalen. These results strongly suggest the presence of a very active (R)-11-lipoxygenase in H. vulgaris. The activity of both R and S enantiomers of synthetic 9-, 11- and 12-HETE and of ‘endogenous’ 11-HETE was studied on tentacle regeneration and bud formation in decapitated Hydra. Although almost all compounds tested inhibited budding, only endogenous 11-HETE and synthetic (R)-11-HETE significantly enhanced the average number of tentacles, thus suggesting that this eicosanoid might be one of the cellular regulators of regeneration in H. vulgaris.

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