CI-949
目录号 : GC31994
CI-949是一种过敏介质释放抑制剂，可抑制组胺(histamine)，白三烯C4/D4(LTC4/LTD4)和血栓素B2(TXB2)的释放，IC50分别为11.4μM，0.5μM和0.1μM。
Cas No.:104961-19-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Inhibition by Cl-949 of LTC4/D4, TXB2, and histamine release from human leukoeytes challenged with anti-lgE. Cells are preincubated at 37°C with Cl-949 (0.1, 1, 10 and 100 μM) for 10 minutes before the addition of anti-lgE. The cells are then challenged with appropriate stimulus in a concentration to obtain histamine release from the ascending portion of the dose-response curve from each donor (or with buffer) and incubated for 50 minutes at 37°C. The reaction is stopped by centrifugation, and the resulting supernatant solutions are decanted and saved for quantitation of allergic mediators. Mediator release and inhibition of mediator release by CI-949 is comparable in ceils prepared by either method[1]. |
Animal experiment: | Guinea pigs[2]Male, Hartley Strain guinea-pigs, weighing 175-250 g are used in these experiments. Actively sensitized guinea-pigs are given i.p. doses of 30, 50, or 100 mg/kg of CI-949 between 20-120 min before aerosol challenge with antigen[2]. |
References: [1]. Conroy MC, et al. Inhibition of histamine, leukotriene C4/D4, and thromboxane B2 release from human leukocytes and human chopped lung mast cells by the allergic mediator release inhibitor, CI-949. J Allergy Clin Immunol. 1990 Dec;86(6 Pt 1):902-8. | |
CI-949 is an allergic mediator release inhibitor, which inhibits histamine, leukotriene C4/D4 (LTC4/LTD4), and thromboxane B2 (TXB2) release with IC50s of 11.4 μM, 0.5 μM and 0.1 μM, respectively.
CI-949 inhibits, in a dose-dependent manner, the release of histamine, leukotriene, and thromboxane from human basophilic leukocytes challenged with anti-IgE. The IC50 for inhibition of histamine release is 11.4 μM. Virtually complete inhibition of histamine release occurs at 100 μM, with negligible inhibition of release <3 μM. Both LTC4/LTD4 and TXB2 release are inhibited at lower concentrations (IC50, 0.5 and 0.1 μM, respectively). Complete inhibition of leukotriene and thromboxane synthesis/release is obtained with 10 and 1 μM of CI-949, respectively. CI-949 is an effective inhibitor of release of all three mediators in response to this stimulus. The IC50s for inhibition of histamine, leukotriene, and thromboxane are 6.3, 2, and 0.1 μM for FMLP challenge[1]. CI-949 effectively inhibits the release of histamine and the synthesis or release of immunoreactive sulfidopeptide leukotrienes C4-D4 and thromboxane B2 from antigen-challenged lung fragments of of actively sensitized guinea-pigs. The IC50s are 26.7±2.8 μM for histamine, 2.7±2.4 μM for leukotriene, and 3.0±1.8 μM for thromboxane[2].
Actively sensitized guinea-pigs are given i .p. doses of 30, 50, or 100 mg/kg of CI-949 between 20-120 min before aerosol challenge with antigen. A dose of 50 mg/kg i.p. of CI-949 protects conscious, aerosol-allergen challenged guinea-pigs for at least 1 h and 100 mg/kg i.p. or per os protects for at least 2 h. The animals are protected from collapse for at least I h after 50 and 100 mg/kg, and 100 mg/kg afforded complete protection up to 2h. An oral dose of 100 mg/kg at 2 h, but not at 4 h before challenge also inhibits collapse. A dose of 100 mg/kg at 4 h and again at 2 h before challenge is more effective than a single dose at 2 h[2].
[1]. Conroy MC, et al. Inhibition of histamine, leukotriene C4/D4, and thromboxane B2 release from human leukocytes and human chopped lung mast cells by the allergic mediator release inhibitor, CI-949. J Allergy Clin Immunol. 1990 Dec;86(6 Pt 1):902-8. [2]. Adolphson RL, et al. CI-949: a new, potential antiallergy compound inhibits antigen-induced allergic reactions in guinea-pigs in vitro and in vivo. Pulm Pharmacol. 1990;3(4):203-8.
| Cas No. | 104961-19-5 | SDF | |
| Canonical SMILES | O=C(C(N1C2=CC=CC=C2)=C(OC(C)C)C3=C1C=CC(OC)=C3)NC4=NN=NN4 | ||
| 分子式 | C20H20N6O3 | 分子量 | 392.41 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.5484 mL | 12.7418 mL | 25.4836 mL |
| 5 mM | 0.5097 mL | 2.5484 mL | 5.0967 mL |
| 10 mM | 0.2548 mL | 1.2742 mL | 2.5484 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
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2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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SARS-CoV-2 Variant Vaccine Boosters Trial: Preliminary Analyses
Background: Protection from SARS-CoV-2 vaccines wanes over time and is compounded by emerging variants including Omicron subvariants. This study evaluated safety and immunogenicity of SARS-CoV-2 variant vaccines. Methods: This phase 2 open-label, randomized trial enrolled healthy adults previously vaccinated with a SARS-CoV-2 primary series and a single boost. Eligible participants were randomized to one of six Moderna COVID19 mRNA vaccine arms (50?g dose): Prototype (mRNA-1273), Omicron BA.1+Beta (1 or 2 doses), Omicron BA.1+Delta, Omicron BA.1 monovalent, and Omicron BA.1+Prototype. Neutralization antibody titers (ID 50 ) were assessed for D614G, Delta, Beta and Omicron BA.1 variants and Omicron BA.2.12.1 and BA.4/BA.5 subvariants 15 days after vaccination. Results: From March 30 to May 6, 2022, 597 participants were randomized and vaccinated. Median age was 53 years, and 20% had a prior SARS-CoV-2 infection. All vaccines were safe and well-tolerated. Day 15 geometric mean titers (GMT) against D614G were similar across arms and ages, and higher with prior infection. For uninfected participants, Day 15 Omicron BA.1 GMTs were similar across Omicron-containing vaccine arms (3724-4561) and higher than Prototype (1,997 [95%CI:1,482-2,692]). The Omicron BA.1 monovalent and Omicron BA.1+Prototype vaccines induced a geometric mean ratio (GMR) to Prototype for Omicron BA.1 of 2.03 (97.5%CI:1.37-3.00) and 1.56 (97.5%CI:1.06-2.31), respectively. A subset of samples from uninfected participants in four arms were also tested in a different laboratory at Day 15 for neutralizing antibody titers to D614G and Omicron subvariants BA.1, BA.2.12.2 and BA.4/BA.5. Omicron BA.4/BA.5 GMTs were approximately one third BA.1 GMTs (Prototype 517 [95%CI:324-826] vs. 1503 [95%CI:949-2381]; Omicron BA.1+Beta 628 [95%CI:367-1,074] vs. 2125 [95%CI:1139-3965]; Omicron BA.1+Delta 765 [95%CI:443-1,322] vs. 2242 [95%CI:1218-4128] and Omicron BA.1+Prototype 635 [95%CI:447-903] vs. 1972 [95%CI:1337-2907). Conclusions: Higher Omicron BA.1 titers were observed with Omicron-containing vaccines compared to Prototype vaccine and titers against Omicron BA.4/BA.5 were lower than against BA.1 for all candidate vaccines. Clinicaltrialsgov: NCT05289037.
Effect of CI-949 and CI-959 on immune function and lymphoid organs in rats
The immunotoxic properties of two experimental antiallergic drugs, CI-949 and CI-959, were investigated. Wistar rats were gavaged once (CI-949) or twice (CI-959) daily for 21 days with the drugs. Immunotoxicity was assessed using the enzyme-linked immunoabsorbant assay (ELISA) for humoral immunity, a delayed-type hypersensitivity (DTH) procedure for cell-mediated immunity, and natural killer cell (NKC) activity to evaluate spontaneous cytotoxicity. Ratios of body weight to spleen, thymus, liver and kidney weights were determined. Routine histopathology was performed on lymphoid tissue and other body organs. Although 100 mg/kg/day of CI-949 had some stimulating effect on antibody production and NKC cytotoxicity, no consistent immunomodulation was apparent. Except for a significant increase in liver weight at the 100 mg/kg dose of CI-949, no other toxic effects were observed. In contrast to CI-949, CI-959 significantly (P less than 0.05) suppressed antibody production at the 100 mg/kg dose and impaired the DTH reaction, although not significantly. Natural killer cell cytotoxicity was unaffected by 100 mg/kg CI-959. Decreased body weight and histopathological lesions were observed in the thymus and spleen of rats administered 100 mg/kg CI-959. These lesions ranged from mild to severe lymphoid depletion which was also reflected in significantly (P less than 0.05) reduced spleen and thymus organ weight to body weight ratios. Since 100 mg/kg of CI-959 produced toxicological and pathological alterations in the exposed rats, these data suggest that CI-959 is not highly or specifically immunotoxic at dosages lower than those that alter conventional toxicological parameters used in new drug testing programs.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of CI-949, a novel antiallergy compound, on host resistance in mice
The effect of CI-949, a novel inhibitor of allergic mediator release, on immune function was assessed with holistic mouse models of immunocompetence. Resistance to the bacterial pathogens Listeria monocytogenes and Streptococcus pneumoniae and the B16F10 melanoma cell line was used to evaluate the potential of CI-949 to affect immune function. CI-949 treatment of female B6C3F1 mice increased pulmonary tumor burden at 100 mg/kg/day in the B16F10 melanoma model, with a no effect level of at least 50 mg/kg/day. A correlation was seen between decreased clearance of the B16F10 cells and increased tumor burden. However, CI-949 produced this effect only at the maximum tolerated dose. No effect of the drug was seen in the S. pneumoniae model. Host resistance to L. monocytogenes was increased after CI-949 administration, with the no adverse effect level in this model being at least equivalent to the top dose of 100 mg/kg/day. Therefore, the immune system does not appear to be adversely affected or to be a specific target for CI-949 even at an overtly toxic dose.
Differential regulation of the activation of human eosinophils, macrophages, and neutrophils: effect of the allergic mediator release inhibitor CI-949
The allergic mediator release inhibitor CI-949 [5-methoxy-3-(1- methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H-indole-2-carbox amide L-arginine salt] was evaluated for its effect on the activation of human eosinophils, macrophages, and neutrophils by the phagocytic stimulus serum-opsonized zymosan (SOZ). CI-949 inhibited the SOZ- stimulated respiratory burst of eosinophils, measured as the generation of superoxide anion, with an IC50 of 22.8 microM. At concentrations of 100 microM, CI-949 had no inhibitory effect against lysosomal enzyme release by these cells. At 100 microM, CI-949 had no inhibitory effect against release of eosinophil peroxidase while inhibiting release of the macrophage lysosomal enzyme N-acetyl-beta-D- glucosaminidase by only 11.7 percent. In contrast, CI-949 inhibited the release of the neutrophil primary granule enzyme myeloperoxidase inhibiting of 21.4 microM, while inhibiting release of lysozyme from lysosomal enzyme release from secondary granules with an IC50 of 99.3 microM. These results demonstrate that oxygen radical generation and lysosomal enzyme release by human eosinophils, macrophages and neutrophils are differentially regulated by CI-949. These results suggest that these inflammatory cells may have distinct stimulus-related coupling mechanisms.
Effects of CI-949, a novel antiallergy agent, on immune function of male Fischer 344 rats
CI-949 is an orally effective inhibitor of allergic mediator release as measured with in vitro and animal models. To assess the effects of CI-949 on immune function, male Fischer 344 rats were evaluated for splenic T- and B-lymphocyte populations, antibody-forming cell response to sheep red blood cells (sRBC), concanavalin A- and pokeweed mitogen-induced lymphocyte proliferation, Natural Killer cell activity and reticuloendothelial system clearance of sRBC. CI-949 was administered by gavage to rats at 25, 50 and 100 mg/kg/day for 14 consecutive days. A vehicle control and two positive controls (cyclosporine A and cyclophosphamide) were run concurrently. CI-949 at 100 mg/kg/day decreased body weight gain and was lethal to 5 of 40 rats. The deaths occurred between days 5 and 12 of study. This overtly toxic dose did not alter splenic cellularity or change the percentages of T- and B-lymphocyte subpopulations. Additionally, CI-949 did not inhibit lymphocyte proliferation or hinder clearance of sRBC by the reticuloendothelial system. Antibody-forming cell response after immunization showed a dose-related increase in the number of immunoglobulin M secreting cells. Based on the results of these assays, the immune system does not appear to be adversely affected by CI-949 even at high doses.