Disease relevance of N-acetyl-N-[(1-ethyl-6-pyridyl)methyl]carbamic acid [2-methoxy-3-(stearylcarbamoyloxy)propyl] ester

• In contrast to the inhibitory effects of depletion of CD4+ T cells and of anti-IL-5 mAb on the second peak of antigen-induced cutaneous eosinophilia, disodium cromoglycate and a selective antagonist for platelet activating factor (PAF) CV-6209 decreased the first peak of OVA-induced cutaneous eosinophilia in the mouse [1].
• Pretreatment with CV-6209 in group 5 resulted in a marked decrease in hemorrhagic discoloration, vascular congestion and histological changes noted with ischemia in group 4 [2].
• In another group of rats, CV-6209 (1.6 mumol/kg) significantly blocked the hypotension induced by repetitive injections of PAF (570 pmol/kg) with an apparent half-life of approximately 180 min [3].
• Thus PAF-induced ocular pruritus was unaffected by the histamine H1-receptor antagonist pyrilamine but was substantially attenuated by the PAF antagonists WEB 2086 and CV-6209 and was virtually abolished by E-6123 [4].
• To evaluate whether PAF is related to the precipitation of pulmonary edema after myocardial ischemia, we studied the effect of a specific PAF antagonist, CV-6209, on the extravascular lung water level measured by the thermal-dye double indicator dilution method, ETV, after coronary ligation in dogs [5].

High impact information on N-acetyl-N-[(1-ethyl-6-pyridyl)methyl]carbamic acid [2-methoxy-3-(stearylcarbamoyloxy)propyl] ester

• Hexamethonium, amiloride, diphenhydramine, or a specific platelet-activating factor antagonist (CV-6209) did not influence the response to endothelin 1 [6].
• Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE [7].
• WEB 2086 and CV 6209 caused concentration-dependent inhibition of both these markers of leukocyte activation [8].
• Bradykinin-induced prostacyclin generation in endothelial cells was markedly reduced by the PAF receptor antagonists WEB 2086 or CV 6209 [8].
• The effects of IL-16 were blocked by CCR3 inhibitors (met-RANTES, anti-CCR3 mAb) and by neutralizing anti-eotaxin and anti-RANTES mAbs, but not by platelet-activating factor receptor antagonists (CV6209, BN52021) [9].

Chemical compound and disease context of N-acetyl-N-[(1-ethyl-6-pyridyl)methyl]carbamic acid [2-methoxy-3-(stearylcarbamoyloxy)propyl] ester

• In rats, post-treatment with CV-6209 reversed the PAF (1 microgram/kg i.v.)-induced hypotension rapidly (ED50, 0.0046 mg/kg i.v.); CV-6209 was 74, 20, 185 and over 2100 times more potent than CV-3988, ONO-6240, Ginkgolide B and etizolam, respectively [10].
• Furthermore, the plasma accumulation of the lysosomal hydrolase, cathepsin D, and a cardiotoxic peptide, myocardial depressant factor (MDF), were also attenuated by CV-6209 in traumatic shock [11].
• In contrast, neither disodium cromoglycate nor a selective antagonist for platelet-activating factor CV-6209 decreased OVA-induced airway eosinophilia in the mouse [12].

Biological context of N-acetyl-N-[(1-ethyl-6-pyridyl)methyl]carbamic acid [2-methoxy-3-(stearylcarbamoyloxy)propyl] ester

• Among the compounds tested, 2-[[N-acetyl-N-[[2-methoxy-3-[ (octadecylcarbamoyl)oxy]propoxy]-carbonyl]amino] methyl]-1-ethylpyridinium chloride (21, CV-6209) was one of the most potent compounds in the in vitro assay (IC50 = 7.5 X 10(-8) M) and the most potent and long-lasting in the in vivo assays [13].
• CV-6209 inhibited [3H]serotonin release from rabbit platelets stimulated with PAF (3 X 10(-8) M) with a similar potency as the inhibition on the platelet aggregation [10].
• 3. Pretreatment with CV-6209, a PAF antagonist, inhibited PAF- but not ACh-induced vasodilation [14].
• Both WEB 2086 and CV 6209 significantly inhibited the respiratory burst and degranulation in response to 400 nM PAF in a dose-dependent manner (10(-8)-10(-5) M) [15].
• Lyso-PAF- and PAF-induced increases in conjunctival microvascular permeability were virtually abolished by the PAF antagonist CV-6209 [16].

Anatomical context of N-acetyl-N-[(1-ethyl-6-pyridyl)methyl]carbamic acid [2-methoxy-3-(stearylcarbamoyloxy)propyl] ester

• We also determined the effect of oxygen removal by clamping the bronchus in advance of pulmonary artery occlusion, intercellular adhesion molecule-1 (ICAM-1) neutralization with monoclonal antibody 1A29, and platelet-activating factor (PAF) receptor antagonist CV6209 on H2O2 production and MVP [17].
• 1. The role of intracellular platelet-activating factor (Paf) in arachidonic acid (AA) mobilization from guinea-pig peritoneal macrophages has been investigated by use of the potent and selective Paf receptor antagonists, WEB 2086 and CV 6209 [18].
• These results suggest that endogenous PAF may play an important role in gastric mucosal injury induced by ischemia-reperfusion, and that CV-6209 exerts its beneficial effect mainly by inhibiting neutrophil superoxide production induced by PAF [19].
• To investigate whether platelet-activating factor (PAF) is a mediator of pulmonary vasoconstrictive and bronchoconstrictive responses after antigen challenge, we administered antigenic erythrocytes after the administration of PAF antagonist (.1 mg/kg; CV6209) [20].
• This augmentation of DNA synthesis in bone marrow cells was abolished by specific PAF antagonists, CV-6209 or FR-900452 [21].

Associations of N-acetyl-N-[(1-ethyl-6-pyridyl)methyl]carbamic acid [2-methoxy-3-(stearylcarbamoyloxy)propyl] ester with other chemical compounds

• The motility was abrogated by addition of a panel of chemically unrelated PAF receptor antagonists (WEB 2170, CV 3988, CV 6209, and BN 52021), suggesting that the synthesized PAF mediates the motogenic effect of Tat [22].
• PCA in W/Wv mice mediated by a low dilution (1:4) of hyperimmune serum to bovine serum albumin of the B6D2F1 mouse origin was markedly suppressed by CV-6209, an antagonist of platelet-activating factor (PAF), but not by antihistamines such as cyproheptadine and oxatomide [23].
• Preincubation of the cells with the PAF receptor antagonist CV6209 (10(-6) M) inhibited the increase in [Ca2+]i. Ca(2+)-free medium (2 mM EGTA) totally abolished the sustained response to PAF, but it only partially inhibited the transient response [24].
• 3. RP 59227, like the reference compounds WEB 2086 and CV-6209, behaved as a competitive antagonist against PAF-evoked platelet aggregation in PRP, WP and dil [25].
• These effects of ET-1 were blocked by a cyclooxygenase inhibitor (indomethacin), a TXA2 synthetase inhibitor (CV-1451) and a specific platelet activating factor (PAF) antagonist (CV-6209) [26].

Gene context of N-acetyl-N-[(1-ethyl-6-pyridyl)methyl]carbamic acid [2-methoxy-3-(stearylcarbamoyloxy)propyl] ester

• Three specific PAF-receptor antagonists, WEB2086, CV3988, and CV6209, reversed this effect of PAF [27].
• This increase was blocked by PAF receptor antagonists, CV 6209 and TCV 309, and by pretreatment with genistein [28].
• Cells were stimulated by Stx1 or Stx2 (5 ng/ml) with or without CV6209 addition (12-100 microg/ml) for various periods of time [29].
• CV-6209, a selective antagonist of platelet-activating factor (PAF), also prevented the activation of t-PA as well as ulcer formation, providing a concept that PAF may be associated with the local fibrinolytic activation which may cause hemorrhagic changes in the gastric mucosal microvasculature [30].
• Decreased mucosal blood flow was attenuated to some extent by the pretreatment with platelet-activating factor (PAF) inhibitor, CV-6209, superoxide dismutase plus catalase or the calcium antagonist, nicorandil [31].

Analytical, diagnostic and therapeutic context of N-acetyl-N-[(1-ethyl-6-pyridyl)methyl]carbamic acid [2-methoxy-3-(stearylcarbamoyloxy)propyl] ester

• A novel, potent, PAF antagonist, CV-6209 (160 nmol/kg or 1.6 mumol/kg) injected after the ligation, significantly retarded the loss of amino-nitrogen and cathepsin D activity in a dose-related manner [3].
• This stimulatory effect was inhibited in a dose-dependent manner by the pretreatment of macrophage/EC cocultures with WEB-2086 or CV-6209, specific platelet-activating factor (PAF)-receptor antagonists, but not by anti-tumor necrosis factor-alpha, anti-interleukin (IL)-1alpha, or anti-IL-1beta [32].
• Furthermore, the increase in cardiac permeability induced in isolated perfused rat hearts undergoing 15 min global ischemia followed by reperfusion was significantly attenuated by CV-6209 (250 nmol/l) [3].
• A control group of mice received i.p. injections of PBS as vehicle while a further two groups were treated either with pyrilamine, a histamine receptor 1 antagonist or with CV6209, a platelet activating factor receptor antagonist [33].
• The intravenous injection of CV-6209, a PAF antagonist, 5 min prior to the stimuli significantly inhibited the DCF activation, the increases in PAF level and MPO activity, the mucosal hemorrhagic change, and the elevation in chemiluminescence activity [34].

References