Characterization of CGS 8515 as a selective 5-lipoxygenase inhibitor using in vitro and in vivo models

Ku, Edmond C.; Raychaudhuri, A.; Ghai, Geetha; Kimble, Earl F.; Lee, Warren H.; Colombo, Carmelo; Dotson, Ronald; Oglesby, Thomas D.; Wasley, Jan W. F.

doi:10.1016/0005-2760(88)90207-x

Cited by 27 publications

(15 citation statements)

References 32 publications

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“…These results are similar to what has been reported with other 5-LOis in this model [3,5]. It has been The assays were based on 14C-AA conversion in guinea pig leukocytes (5-LO) or partially purified enzymes isolated from rat seminal vesicles (CO), human platelets (12-LO and TxA2) and human leukocytes (15-LO) or whole blood stimulated with A23187 to produce LTB4.…”

Section: Resultssupporting

confidence: 88%

See 1 more Smart Citation

CGS 26529: The biological profile of a novel, orally active 5-lipoxygenase inhibitor with an extended duration of action

Kimble¹,

Kowalski²,

Peters³

et al. 1995

Inflamm Res

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Section: Resultssupporting

confidence: 88%

“…The in vitro cellular, enzyme and whole blood assays for determination of 5-HETE, LTB4, cyclooxygenase (CO), thromboxane synthase (TxA2), 12-1ipoxygenase (12-LO) and 15-1ipoxygenase (15-LO) have been described previously [3,4].…”

Section: In Vitro Studiesmentioning

confidence: 99%

CGS 26529: The biological profile of a novel, orally active 5-lipoxygenase inhibitor with an extended duration of action

Kimble¹,

Kowalski²,

Peters³

et al. 1995

Inflamm Res

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“…The accumulation of exudate fluid and leukocytes into the pleural cavity in response to carrageenin injection appears to be regulated by metabolites of AA for the following reasons. Carrageenin injection causes accumulation of PGE2 (Katori et al, 1978), LTB4 (Flower et al, 1986) and LTC4/D4 (Ueno et al, 1983), and many inhibitors of cyclooxygenase, 5-lipoxygenase, or both suppress both plasma exudation and leukocyte migration induced by carrageenin (Ashida et al, 1983;Ku et al, 1988). YM-26734 also inhibited accumulation of exudate fluid and leukocytes into the pleural cavity, suggesting that extracellular group II PLA2 may play a role in this inflammatory process.…”

Section: Discussionmentioning

confidence: 96%

Suppression of inflammatory responses to 12‐O‐tetradecanoylphorbol‐13‐acetate and carrageenin by YM‐26734, a selective inhibitor of extracellular group II phospholipase A₂

Miyake

Yamamoto

Kubota

et al. 1993

British J Pharmacology

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1 YM-26734 [4-(3,5-didodecanoyl-2,4,6-trihydroxyphenyl)-7-hydroxy-2-(4-hydroxyphenyl)chroman] dosedependently inhibited the activities of extracellular phospholipase A2 (PLA2): rabbit platelet-derived group II and porcine pancreas-derived group I PLA2, with ICs values of 0.085 (0.056-0.129, n = 5) and 6.8 (5.0-9.6, n = 5) ylM, respectively. 2 In contrast, YM-26734 did not reduce the activity of intracellular PLA2 prepared from mouse macrophages, which preferentially hydrolyzed arachidonoyl phospholipids at concentrations up to 50SAM. YM-26734 also showed no effect against either sheep seminal vesicle cyclo-oxygenase or rat leukocyte 5-lipoxygenase. kg-', i.v.) than in the control group (0.43 ± 0.02 vs 0.59 ± 0.03 g per cavity and 3.8 ± 0.2 vs 4.9 ± 0.3 x 107 cells per cavity, respectively; n = 5). 6 These results suggest that YM-26734 is a potent and competitive inhibitor of extracellular PLA2 with selectivity for group II PLA2, and that the inhibition of group II enzymes activity may cause the suppression of inflammatory responses to TPA and carrageenin.

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“…There may be a difference of 5-lipoxygenase activity itself or a difference of the sensitiv ities of 5-lipoxygenase in human lung and guinea-pig lung. Ku et al [24] also reported that CGS 8515 (a selective 5-lipoxygenase inhibitor) inhibited A23187-induccd forma tion of LT products in whole blood with IC50 values of 0.8 and 4 uA/, respectively, for man and rat.…”

Section: Discussionmentioning

confidence: 97%

Effects of the New 5-Lipoxygenase Inhibitor E6080 on Leukotriene Release in vitro

Sakuma¹,

Katayama²,

Tsunoda³

et al. 1992

Int Arch Allergy Immunol

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Fundamental studies were conducted to examine the release of histamine and leukotriene (LT) C₄ from lung fragments of guinea pigs and the effects of E6080 on the release of LTB₄ and LTC₄ from lung fragments or inflammatory cells. The release of histamine and LTs showed large interindividual variations and a marked dependence on experimental conditions. Addition of 10 mML-cysteine significantly increased LTC₄ release compared with that in its absence (about 1.7 times, in terms of mean value). E6080 inhibited antigen-stimulated LTB₄ and LTQ release from passively sensitized human (IC₅₀: LTB₄ 0.08 µM, LTC₄ 0.2 µM) and guinea-pig lung fragments (IC₅₀: LTQ 1.1 µM). The LTB₄ and LTQ releases from healthy human polymorphonuclear leukocytes (calcium ionophore A23187) and from allergic patients’ leukocytes (basophils, antigen) were inhibited by E6080 with IC₅₀ values of below 1.0 µM Furthermore, the LTQ release from rat alveolar macrophages (silica particles) was inhibited by E6080 with an IC₅₀ of 0.2 µM The potent inhibition by E6080 might be a result of the inhibition of 5-lipoxygenase, since 5-lipoxygenase in rat basophilic leukemia cell was inhibited by E6080 with an IC₅₀ of 0.2 µM The results confirm the potent inhibitory effects of E6080 on the release of LTs.

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Characterization of CGS 8515 as a selective 5-lipoxygenase inhibitor using in vitro and in vivo models

Cited by 27 publications

References 32 publications

CGS 26529: The biological profile of a novel, orally active 5-lipoxygenase inhibitor with an extended duration of action

CGS 26529: The biological profile of a novel, orally active 5-lipoxygenase inhibitor with an extended duration of action

Suppression of inflammatory responses to 12‐O‐tetradecanoylphorbol‐13‐acetate and carrageenin by YM‐26734, a selective inhibitor of extracellular group II phospholipase A₂

Effects of the New 5-Lipoxygenase Inhibitor E6080 on Leukotriene Release in vitro

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Characterization of CGS 8515 as a selective 5-lipoxygenase inhibitor using in vitro and in vivo models

Cited by 27 publications

References 32 publications

CGS 26529: The biological profile of a novel, orally active 5-lipoxygenase inhibitor with an extended duration of action

CGS 26529: The biological profile of a novel, orally active 5-lipoxygenase inhibitor with an extended duration of action

Suppression of inflammatory responses to 12‐O‐tetradecanoylphorbol‐13‐acetate and carrageenin by YM‐26734, a selective inhibitor of extracellular group II phospholipase A2

Effects of the New 5-Lipoxygenase Inhibitor E6080 on Leukotriene Release in vitro

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Suppression of inflammatory responses to 12‐O‐tetradecanoylphorbol‐13‐acetate and carrageenin by YM‐26734, a selective inhibitor of extracellular group II phospholipase A₂