Pharmacological profiles of a potential LTB4-antagonist, SM-9064

Namiki, Mitsuo; Igarashi, Y.; Sakamoto, Kimiko; Nakamura, Toshio; Koga, Yoshihiko

doi:10.1016/s0006-291x(86)80530-7

Cited by 25 publications

(4 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BWB70C was also without effect on the carrageenin-induced paw oedema, confirming previous studies with other selective 5-LO inhibitors (Higgs et al, 1988). Although Namiki et al (1986) reported that LTB4 was chemotactic for rat neutrophils in vitro, others have failed to demonstrate such an effect (Kreisle et al, 1985, Kopp et al, 1985. Moreover, binding studies suggest that rat neutrophils lack the low affinity LTB4 receptor which is thought to mediate chemotaxis (Kreisle et al, 1985), which therefore may explain the lack of activity of 5-LO inhibitors in these neutrophil-dependent models of inflammation.…”

Section: Discussionsupporting

confidence: 76%

Role of oxygen radicals and arachidonic acid metabolites in the reverse passive Arthus reaction and carrageenin paw oedema in the rat

Boughton‐Smith

Deakin

Follenfant

et al. 1993

British J Pharmacology

111

View full text Add to dashboard Cite

1 The role of arachidonic acid metabolites and oxygen radicals in carrageenin-induced rat paw oedema and dermal reverse passive Arthus reaction (RPA) have been investigated. 2 Indomethacin (10 mg kg-', p.o.) inhibited carrageenin paw oedema when administered 30 min before, but not 2 h after carrageenin. BWB70C (10 mg kg-', p.o.), a selective inhibitor of 5-lipoxygenase, had no effect whether administered before or after carrageenin. Administration of both indomethacin and BWB70C had no greater anti-inflammatory effect than indomethacin alone. 3 BW755C (20 mg kg-, p.o.), which inhibits the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism, or superoxide dismutase-polyethylene glycol conjugate (SOD-PEG, 3000 u, i.v.) inhibited carrageenin paw oedema whether administered either 30 min before, or 2 h after carrageenin.4 Pretreatment with dexamethasone (0.1 mg kg-') or colchicine (2 mg kg-'), likewise suppressed carrageenin paw oedema. 5 BW755C (25-100mgkg-', p.o.) dose-dependently reduced plasma leakage in the RPA, whereas indomethacin (5mgkg-', p.o.) or BWB70C either alone or in combination, did not. 6 SOD-PEG (300-3000 u, i.v.) dose-dependently inhibited plasma leakage in the RPA. In addition, the iron chelator and peroxyl radical scavenger, desferrioxamine (200mgkg-', s.c.) also inhibited plasma leakage. 7 Pretreatment with dexamethasone (0.1 mg kg-') or colchicine (1 mg kg-l) reduced the plasma leakage in RPA, whereas MK-886 (10mgkg-1) had no effect. 8 These results indicate an important role for oxygen radicals but not arachidonic acid metabolites in the maintenance of carrageenin paw oedema and the plasma leakage in RPA. Furthermore, the results suggest that the anti-inflammatory actions of BW755C can be dissociated from its effects on arachidonic acid metabolism and are attributed to its anti-oxidant activity.

show abstract

Section: Discussionsupporting

confidence: 76%

Role of oxygen radicals and arachidonic acid metabolites in the reverse passive Arthus reaction and carrageenin paw oedema in the rat

Boughton‐Smith

Deakin

Follenfant

et al. 1993

British J Pharmacology

111

View full text Add to dashboard Cite

show abstract

“…Methyl 5-Hydroxy-6-[7-[l-[[dimethyI(l,l-dimethylethyl)silyl]oxy]nonyl]quinolin-2-yl]hexanoate (10). A solution of pyridine (1.1 mL).…”

Section: Methodsmentioning

confidence: 99%

Synthesis of structural analogs of leukotriene B4 and their receptor binding activity

Kingsbury

Pendrak²,

Leber³

et al. 1993

J. Med. Chem.

View full text Add to dashboard Cite

Structural analogs of leukotriene B4 (LTB4) were designed using a preferred conformation of LTB4 (1). Appending an aromatic ring scaffold between LTB4 carbons 7 and 11 led to quinoline analogs 3 and 15. A similar modification to the LTB4 structure between carbons 7 and 9 led to the pyridine analogs 41 and 46. The compounds of this study were evaluated in receptor binding assays using [3H]LTB4 and intact human DMSO differentiated U-937 cells. The first analog prepared, quinoline 3, displayed moderate potency in the LTB4 receptor binding assay (Ki = 0.9 microM). Modification of 3 by appending an aromatic ring between carbons 2 and 4 of the acid side chain produced a dramatic increase in receptor binding (15, Ki = 0.01 microM); a further improvement in receptor binding was achieved in the pyridine series (e.g., 41; Ki = 0.001 microM). The LTB4 receptor agonist/antagonist activity of the test compounds was determined using a functional assay that relies upon intracellular calcium mobilization induced by LTB4. Of the analogs prepared in this report only 47 demonstrated LTB4 receptor antagonist activity.

show abstract

“…However, information on agents which either selectively inhibit the biosynthesis of LTB, or antagonise its effects at the receptor level is limited. Previous studies [25, 261 …”

mentioning

confidence: 98%

“…However, information on agents which either selectively inhibit the biosynthesis of LTB, or antagonise its effects at the receptor level is limited. Previous studies [25,261 have suggested that the development of structural analogues of LTB, is a rational approach to the development of a LTB, receptor antagonist. We now report on the structure/activity relationship of synthetic LTB, analogues, using chemotactic, lysosomal-enzyme release and receptor-binding assays.…”

mentioning

confidence: 99%

Structure/activity relationship of leukotriene B₄ and its structural analogues in chemotactic, lysosomal‐enzyme release and receptor‐binding assays

Soyombo

Spur

Soh

et al. 1993

European Journal of Biochemistry

View full text Add to dashboard Cite

The biological activities of chemically synthesized leukotriene B, and eight structural analogues have been studied using chemotaxis, lysosomal-enzyme release and receptor-binding assays on human neutrophils. The results show that increasing the number of double bonds between C14 and C20, having triple bonds at C6 or C14, substitution of the primary carboxyl group at C1, changing the geometry of the double bond at C6 from the cis to trans configuration and changing the chirality of the hydroxyl group at C12 from the R to the S configuration result in substantial loss of both biological activity and the capacity to bind to the LTB, recognition site in parallel. We suggest that the functional epitopes of 5S, 12R-dihydroxy-6,14-cis-8,lO-truns-icosatetraenoic acid (LTB,) are either the same, or reside in the same domain as the binding site for the LTB, receptor. Development of LTB, antagonists to the high-affinity LTB, receptor, based on the structure of LTB,, is unlikely to be successful.Arachidonic acid is released from membrane phospholipids upon stimulation and is transformed via 5-hydroperoxy-6,8,11,14-icosatetraenoic acid (5-HPETE) by the 5-lipoxygenase enzyme [l-31 into an unstable epoxide, leukotriene A, (LTA,; 5,6-oxido-7,9,11,14-icosatetraenoic acid) [4]. LTA, is formed from 5-HPETE by abstraction of a hydrogen at ClO and elimination of a hydroxyl anion from the hydroperoxy group. LTA, undergoes either spontaneous, non-enzymic hydrolysis to form several stereochemically distinct 5,12-dihydroxy-icosatetraenoic acids (5,12-diHETE) or is enzymically catalyzed by the hydrolase enzyme to form leukotriene B, (LTB, ; 5S, 12R-dihydroxy-6,14-cis-8,1 O-trunsicosatetraenoic acid), a specific form of 5,12-diHETE [5, 61. Conjugation of LTA, with glutathione at the C6 position, by the glutathione-S-transferase enzyme LTC, synthetase, leads to the formation of LTC, (5S-hydroxy-GR-glutathionyl-7,9-truns-ll,14-cis-icosatetraenoic acid) [7, 81. LTC, is metabolically altered by successive elimination of a y-glutamyl residue, then glycine, to form its 6-cysteinylglycyl analogue, LTD, [9] and its 6-cysteinyl analogue, LTE, [lo] respectively. The structure of LTB, is 5S,12R-dihydroxy-6,14-cis-8,1O-truns-icosatetraenoic acid (compound I) [ll]. It is synthesized by human neutrophils, monocytes and alveolar macrophages in response to a wide variety of stimuli Abbreviations. PMN, polymorphonuclear cells ; HPETE, hydroperoxyicosatetraenoic acid; LTA,, 5,6-oxido-7,9,11,14-icosatetraenoic acid; diHETE, dihydroxyicosatetraenoic acids ; DMA, dimethylamide; LTB,, 5s. 12R-dihydroxy-6,14-cis-8,lO-trunL~-icosatetraenoic acid (compound 1); LTC,, SS-hydroxy-6R-glutathionyl-7,9-trans-11,14-cis-icosatetraenoic acid; IC,,, concentration at which half of the response is inhibited; fmet, formylmethionyl; HBSS, Hanks' balanced-salt solution; HPF, High-power field; compounds I-IX, the structures and chemical formulae are shown in Fig. 1. and is a potent chemotactic agent for neutrophils [12]. It induces aggregation of polymorphonuclear cells (P...

show abstract

Pharmacological profiles of a potential LTB4-antagonist, SM-9064

Cited by 25 publications

References 17 publications

Role of oxygen radicals and arachidonic acid metabolites in the reverse passive Arthus reaction and carrageenin paw oedema in the rat

Role of oxygen radicals and arachidonic acid metabolites in the reverse passive Arthus reaction and carrageenin paw oedema in the rat

Synthesis of structural analogs of leukotriene B4 and their receptor binding activity

Structure/activity relationship of leukotriene B₄ and its structural analogues in chemotactic, lysosomal‐enzyme release and receptor‐binding assays

Contact Info

Product

Resources

About

Pharmacological profiles of a potential LTB4-antagonist, SM-9064

Cited by 25 publications

References 17 publications

Role of oxygen radicals and arachidonic acid metabolites in the reverse passive Arthus reaction and carrageenin paw oedema in the rat

Role of oxygen radicals and arachidonic acid metabolites in the reverse passive Arthus reaction and carrageenin paw oedema in the rat

Synthesis of structural analogs of leukotriene B4 and their receptor binding activity

Structure/activity relationship of leukotriene B4 and its structural analogues in chemotactic, lysosomal‐enzyme release and receptor‐binding assays

Contact Info

Product

Resources

About

Structure/activity relationship of leukotriene B₄ and its structural analogues in chemotactic, lysosomal‐enzyme release and receptor‐binding assays