Quinotolast sodium (FR71021)
(Synonyms: FR71021) 目录号 : GC31820
浓度范围为 1-100 μg/mL 的 Quinotolast sodium (FR71021) 以浓度依赖性方式抑制组胺、LTC4 和 PGD2 的释放。
Cas No.:101193-62-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | Mast cells are obtained after the culture of bone marrow cells from the femurs of female BDF1 mice in the presence of conditioned medium from WEHI-3 cells containing interleukin 3. The cells are suspended with Tyrode's buffer (137 mM NaCI, 2.7 mM KC1, 1.8 mM CaCl2, 1 mM MgCl2, 0.4 mM NaH2PO4, 11.9 mM NaHCO3, 5.6 mM glucose) containing 0.1% gelatin and are sensitized with mouse monoclonal anti-DNP IgE (50 μg/106 cells). Then the cells are washed and resuspended with Tyrode's buffer containing 0.25% BSA. The cells (2×106 cells) are incubated for 5 min at37°C and challenged with TNP-BSA (2 ng BSA/mL). Quinotolast (0.1, 1, 10, 100 ug/mL) is added to the reaction tube simultaneously with the antigen. Ten minutes later, the reaction is stopped by the addition of EDTA (2.7 mM). pLTs in the cell supernatant sre quantified as immunoreactive leukotriene C4 (iLTC4) with a leukotriene C4/D4/E4[3H] assay system. % Inhibition is calculated in each experiment from the amount of immunoreactive leukotriene C4 (iLTC4)[2]. |
Animal experiment: | Rats [2]Rats (8 week-old) are used. To study the presence of tachyphylaxis by Quinotolast, Quinotolast (0.001, 0.01, 0.1, 1,10 and 100 mg/kg) is given i.v. in a large dose 30 min before challenge, and again at a smaller dose simultaneously with the antigen challenge. |
References: [1]. Okayama Y, et al. Inhibition of histamine and eicosanoid release from dispersed human lung cells in vitro byquinotolast. Jpn J Pharmacol. 1995 Dec;69(4):375-80. | |
Quinotolast sodium in the concentration range of 1-100 μg/mL inhibits histamine, LTC4 and PGD2 release in a concentration-dependent manner.
Quinotolast inhibits the release of histamine and the generation of leukotriene (LT) C4 and prostaglandin (PG) D2 from dispersed human lung cells. Quinotolast (100 μg/mL) significantly inhibits PGD2 and LTC4 release. Quinotolast inhibits PGD2 release by 100% and LTC4 release by 54%. The inhibitory effect of Quinotolast on histamine release from dispersed lung cells is largely independent of the preincubation period, no tachyphylaxis being observed. Quinotolast shows a significant inhibition of inflammatory mediators from human dispersed lung cells[1]. Quinotolast also shows strong inhibitory effects on histamine and peptide leukotrienes release from guinea pig lung fragments or mouse cultured mast cells. Quinotolast concentration-dependently inhibits pLTs release from cultured mast cells. The IC50 value for Quinotolast is 0.72 μg/mL[2].
Quinotolast potently inhibits such type I allergic reactions as passive cutaneous anaphylaxis (PCA) and anaphylactic bronchoconstriction in rats by both intravenous and oral dosing. When Quinotolast is given i.v. to rats, Quinotolast, dose-dependently inhibits PCA. The doses of Quinotolast required to inhibit the reaction by 50% (ED50) is 0.0063 mg/kg. Given p.o., Quinotolast inhibits the reaction. ED50 value for Quinotolast is 0.0081 mg/kg. Although almost complete inhibition is observed with Quinotolast at a dose of 0.32 mg/kg, its effect is slightly attenuated at a dose of 1 mg/kg[2].
[1]. Okayama Y, et al. Inhibition of histamine and eicosanoid release from dispersed human lung cells in vitro byquinotolast. Jpn J Pharmacol. 1995 Dec;69(4):375-80. [2]. Kobayashi K, et al. Effects of quinotolast, a new orally active antiallergic drug, on experimental allergic models. Jpn J Pharmacol. 1993 Sep;63(1):73-81.
| Cas No. | 101193-62-8 | SDF | |
| 别名 | FR71021 | ||
| Canonical SMILES | O=C(NC1=NN=NN1)C2=CC(OC3=CC=CC=C3)=C4N(C2=O)C=CC=C4.[Na] | ||
| 分子式 | C17H12N6NaO3 | 分子量 | 371.31 |
| 溶解度 | DMSO : 115 mg/mL (309.71 mM; ultrasonic and warming and heat to 60°C) | 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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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6932 mL | 13.4658 mL | 26.9317 mL |
| 5 mM | 0.5386 mL | 2.6932 mL | 5.3863 mL |
| 10 mM | 0.2693 mL | 1.3466 mL | 2.6932 mL |
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Inhibition of histamine and eicosanoid release from dispersed human lung cells in vitro by quinotolast
We have examined the effects of a new anti-allergic drug, quinotolast [sodium 5-(4-oxo-1-phenoxy-4H-quinolizine-3-carboxamido) yetrazolate monohydrate], in inhibiting the release of histamine and the generation of leukotriene (LT) C4 and prostaglandin (PG) D2 from dispersed human lung cells and compared this with those of its active metabolite in the rat, hydroxy quinotolast, and reference drugs, tranilast and sodium cromoglycate (SCG). Quinotolast in the concentration range of 1-100 micrograms/ml inhibited histamine and LTC4 release in a concentration-dependent manner. The inhibitory effect of quinotolast on histamine release from dispersed lung cells was largely independent of the preincubation period, no tachyphylaxis being observed. Hydroxy quinotolast and tranilast showed a weak inhibition of histamine release only when the drugs were added to the cells simultaneously with anti-IgE challenge. Quinotolast, 100 micrograms/ml, and SCG, 1 mM, significantly inhibited PGD2 and LTC4 release. Quinotolast inhibited PGD2 release by 100% and LTC4 release by 54%, whereas SCG inhibited PDG2 release by 33% and LTC4 release by 100%. No cross-tachyphylaxis between quinotolast and SCG was observed. The results demonstrated that quinotolast showed a significant inhibition of inflammatory mediators from human dispersed lung cells, suggesting that quinotolast is a good candidate for a clinical anti-allergic drug.
Effects of quinotolast, a new orally active antiallergic drug, on experimental allergic models
The effects of a new antiallergic drug, quinotolast [sodium 5-(4-oxo-1-phenoxy-4H-quinolizine-3-carboxamido)tetrazolate monohydrate], were studied and compared with those of tranilast, amlexanox, pemirolast, repirinast and disodium cromoglycate (DSCG) in experimental allergic models. Quinotolast potently inhibited such type I allergic reactions as passive cutaneous anaphylaxis (PCA) and anaphylactic bronchoconstriction in rats by both intravenous and oral dosing. All of these effects were stronger than those of the reference drugs tested. Quinotolast inhibited histamine release from rat peritoneal cells, but it had no antagonistic effect on histamine-, serotonin-, platelet activating factor- or bradykinin-induced cutaneous reactions in rats. Moreover, it was clearly demonstrated that quinotolast and DSCG had a cross tachyphylaxis to inhibit PCA in rats, suggesting that these drugs, at least in part, share the same mechanism of action. Furthermore, quinotolast potently inhibited PCA in guinea pigs in which DSCG and other reference drugs showed poor inhibitory activity. Quinotolast also showed stronger inhibitory effects on histamine and peptide leukotrienes release from guinea pig lung fragments or mouse cultured mast cells than the other drugs tested. Thus, the effect of quinotolast on type I allergic reaction would seem to be based on an inhibition of mediator release from inflammatory cells including mast cells. The results suggest that quinotolast will be beneficial in the treatment of type I allergy-related diseases.
Kinetic study of the transformation from tetrahydrate to monohydrate of a new antiallergic, sodium 5-(4-oxo-phenoxy-4H-quinolizine-3-carboxamide)-tetrazolate
Two hydrates (tetrahydrate, I, and monohydrate, II) of a new antiallergic, sodium 5-(4-oxo-phenoxy-4H-quinolizine-3-carboxamide)-tetrazolate (FR71021), were prepared and characterized by means of infrared spectrometry, thermal analysis, and power X-ray diffraction spectrometry. While I was confirmed to dehydrate readily resulting in an anhydrate form (noncrystalline form) below its critical relative humidity for dehydration, I was also transformed into II under humid conditions. The transformation kinetics from I to II were investigated under varying temperature and humidity conditions by a powder X-ray diffraction technique. The transformation mechanism followed a zero-order reaction, and the apparent transformation rate constant (k) could be described as a function of water vapor pressure (P), temperature (T), and the interaction orders between water vapor pressure and the samples (s): k = A.exp(-Ea/RT).Ps, where Ea is the activation energy and R is the gas constant.
Utility of hepatocytes in predicting drug metabolism: comparison of hepatic intrinsic clearance in rats and humans in vivo and in vitro
We investigated hepatic in vitro intrinsic clearance (CL(int,in vitro)) in freshly isolated or cryopreserved hepatocytes and compared with CL(int,in vivo) by using nine model compounds, FK1052, FK480, diazepam, diltiazem, troglitazone, quinotolast, FK079, zidovudine, and acetaminophen, in rats and humans. The compounds showed a broad range of in vivo hepatic extraction ratios (rat, 0.05-0.93; humans, 0.03-0.76) and were metabolized by hepatic P450, UDP-glucuronosyltransferase, sulfotransferase, and/or esterase. CL(int,in vitro) was determined from substrate disappearance rate at 1 microM in hepatocytes. CL(int,in vivo) was calculated from in vivo pharmacokinetic data using two frequently used mathematical models (the well stirred and dispersion models). When estimating rat CL(int,in vitro) in freshly isolated hepatocytes, the rat scaling factor values (CL(int,in vivo)/CL(int,in vitro)) showed marked difference among the model compounds (0.2-73.1-fold). The rat CL(int,in vitro) values in freshly isolated hepatocytes were in good agreement with these in cryopreserved hepatocytes. Human CL(int,in vitro) were determined by use of cryopreserved hepatocytes. When human CL(int,in vitro) was regarded as the predicted CL(int,in vivo), the observed and predicted CL(int,in vivo) for FK1052, FK480, troglitazone, and FK079 differed markedly (12.4-199.0-fold). In contrast, using human CL(int,in vitro) corrected with the rat scaling factors yielded better predictions of CL(int,in vivo) that were mostly within 5-fold of the actual values. These results make the evaluation using hepatocytes more useful and provide a basis for predicting hepatic clearance using hepatocytes.
[Effects of a novel orally-active antiallergic drug, quinotolast (FK021), on airway clearance]
The effects of a novel antiallergic drug, quinotolast (FK021, sodium 5-(4-oxo-1-phenoxy-4H-quinolizine-3-carboxamido) tetrazolate monohydrate), on airway clearance was studied in comparison with those of tranilast (an orally-active antiallergic drug). FK021 (10 mg/kg, p.o.) did not influence the rabbit airway secretion, whereas tranilast (100 mg/kg, p.o.) caused a slight suppression. Neither FK021 (10(-10)-10(-5) g/ml) nor tranilast (10(-6), 10(-4) g/ml) had any effect on pulmonary surfactant secretion in rat type II pneumocytes. FK021 (10 mg/kg, p.o.) caused a significant increase in the mucociliary transport rate in quails, whereas tranilast (320 mg/kg, p.o.) had no effect. Antitussive effects were examined in normal guinea pigs and guinea pigs made bronchitic by an exposure to SO2. FK021 (10 mg/kg, p.o.) and tranilast (320 mg/kg, p.o.) significantly depressed the cough reflex induced by citric acid in normal animals. FK021 (32 mg/kg, p.o.), but not tranilast (320 mg/kg, p.o.), showed antitussive effects on citric acid-induced cough in bronchitic animals. These results suggest that FK021 may have favorable effects on expectoration and cough reflex observed in the patients with chronic obstructive pulmonary diseases such as asthma.