Carbazeran
(Synonyms: 卡巴折伦) 目录号 : GC41449
An inhibitor of PDE2 and PDE3
Cas No.:70724-25-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >97.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Carbazeran is an inhibitor of phosphodiesterase 2 (PDE2) and PDE3. It inhibits cAMP hydrolysis (IC50 = 4.1 µM in rabbit heart ventricles) selectively over cGMP hydrolysis (IC50 = 171 µM). It induces positive inotropic (EC50 = 100 µM) and negative chronotropic effects in isolated rabbit papillary muscle and right atria, respectively. Carbazeran is also a substrate for the enzyme aldehyde oxidase (AOX1), which is involved in the metabolism of xenobiotics.
| Cas No. | 70724-25-3 | SDF | |
| 别名 | 卡巴折伦 | ||
| Canonical SMILES | COC1=C(OC)C=C(C=NN=C2N3CCC(OC(NCC)=O)CC3)C2=C1 | ||
| 分子式 | C18H24N4O4 | 分子量 | 360.4 |
| 溶解度 | Chloroform: Slightly Soluble,Methanol: Slightly Soluble | 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 | 2.7747 mL | 13.8735 mL | 27.7469 mL |
| 5 mM | 0.5549 mL | 2.7747 mL | 5.5494 mL |
| 10 mM | 0.2775 mL | 1.3873 mL | 2.7747 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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。
1. 首先保证母液是澄清的；
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Human Aldehyde Oxidase 1-Mediated Carbazeran Oxidation in Chimeric TK-NOG Mice Transplanted with Human Hepatocytes
Drug Metab Dispos 2020 Jul;48(7):580-586.PMID:32357972DOI:10.1124/dmd.120.091090.
Carbazeran is a potent phosphodiesterase inhibitor with species-dependent metabolic profiles in rats, dogs, and humans. In this study, we investigated the aldehyde oxidase (AOX)-mediated oxidation of Carbazeran to 4-oxo derivatives in chimeric NOD/Shi-scid IL2 receptor gamma-null mice expressing a herpes simplex virus type 1 thymidine kinase transgene with humanized livers (humanized-liver mice). Liver cytosolic fractions from humanized-liver mouse effectively catalyzed Carbazeran 4-oxidation with high affinity for the substrate, similar to those of the human liver cytosolic fractions and recombinant human AOX1 protein. Furthermore, hepatocytes prepared from humanized-liver mice and humans also exhibited substantial metabolism via Carbazeran 4-oxidation. After a single oral administration of Carbazeran (10 mg/kg), plasma levels of 4-oxo-carbazeran, N-desethyl-4-oxo-carbazeran, and 6,7-dimethoxy-1-[4-(hydroxy)-piperidino]-4-phthalazinone (three human metabolites formed via 4-oxidation) were higher in humanized-liver mice than in the control mice. In contrast, plasma levels of O-desmethylcarbazeran (a major metabolite in dogs) in control mice were higher than those in the humanized-liver mice. Relative excreted amounts of the three 4-oxidation-derived human-specific metabolites in the urine and feces were greater for humanized-liver mice than control mice, whereas the relative excreted amounts of O-desmethylcarbazeran were predominant in the urine and feces of control mice. Thus, the production of Carbazeran 4-oxo derivatives was elevated in humanized-liver mice compared with control mice, in agreement with our in vitro enzyme-mediated oxidation data. These results suggest that hepatic human AOX1 functions in humanized-liver mice at the in vivo level and that humanized-liver mice may be useful for predicting drug metabolism in humans, at least with regard to human AOX1-dependent metabolism. SIGNIFICANCE STATEMENT: We found that the production of Carbazeran 4-oxo derivatives was higher in humanized-liver mice than in control mice. These results were supported by the fact that Carbazeran was rapidly metabolized to 4-oxo-carbazeran in humanized-liver mouse hepatocytes expressing human aldehyde oxidase 1. These results suggest that human aldehyde oxidase 1 is functional in humanized-liver mice in vivo and that chimeric NOD/Shi-scid IL2 receptor gamma-null mice expressing a herpes simplex virus type 1 thymidine kinase transgene transplanted with human hepatocytes may be a suitable model animal for predicting aldehyde oxidase-dependent biotransformation of drugs in humans.
Evaluation of Carbazeran 4-Oxidation and O 6-Benzylguanine 8-Oxidation as Catalytic Markers of Human Aldehyde Oxidase: Impact of Cytosolic Contamination of Liver Microsomes
Drug Metab Dispos 2019 Jan;47(1):26-37.PMID:30337443DOI:10.1124/dmd.118.082099.
The present study investigated the contribution of microsomal cytochrome P450 and cytosolic aldehyde oxidase-1 (AOX-1) to Carbazeran 4-oxidation and O 6-benzylguanine 8-oxidation in human liver microsomal, cytosolic, and S9 fractions. Incubations containing Carbazeran and human liver microsomes with or without exogenously added NADPH yielded comparable levels of 4-oxo-carbazeran. O 6-Benzylguanine 8-oxidation occurred in microsomal incubations, and the extent was increased by NADPH. Human recombinant CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 did not catalyze Carbazeran 4-oxidation, whereas CYP1A2 was highly active in O 6-benzylguanine 8-oxidation. 1-Aminobenzotriazole, a pan-cytochrome P450 inhibitor, decreased O 6-benzylguanine 8-oxidation, but not Carbazeran 4-oxidation, in microsomal incubations, whereas 1-aminobenzotriazole and furafylline (a CYP1A2-selective inhibitor) did not inhibit Carbazeran 4-oxidation or O 6-benzylguanine 8-oxidation in human liver S9 fraction. Carbazeran 4-oxidation in incubations containing human liver microsomes (from multiple donors and commercial suppliers) was attributed to microsomal preparations contaminated with AOX-1, as suggested by liver microsomal experiments indicating a decrease in Carbazeran 4-oxidation by an AOX-1 inhibitor (hydralazine), and to detection of AOX-1 protein (at one-third the level of that in liver cytosol). Cytosolic contamination of liver microsomes was further demonstrated by the formation of dehydroepiandrosterone sulfate (catalyzed by cytosolic sulfotransferases) in liver microsomal incubations containing dehydroepiandrosterone. In conclusion, Carbazeran 4-oxidation and O 6-benzylguanine 8-oxidation are enzyme-selective catalytic markers of human AOX-1, as shown in human liver S9 fraction expressing cytochrome P450 and AOX-1. This study highlights the negative impact of cytosolic contamination of liver microsomes on the interpretation of reaction phenotyping data collected in an in vitro study performed in microsomal fractions.
Oxidative metabolism of Carbazeran in vitro by liver cytosol of baboon and man
Xenobiotica 1985 Mar;15(3):237-42.PMID:4024658DOI:10.3109/00498258509045354.
The metabolism of Carbazeran has been investigated in vitro using liver cytosol from dog, baboon and man. Carbazeran was not metabolized in cytosol prepared from dog liver but was rapidly metabolized to a single product in baboon- and human-liver cytosol. The product was identified as 4-hydroxy Carbazeran. The enzyme responsible for the 4-hydroxylation of Carbazeran in vitro was shown by the use of inhibitors to be liver aldehyde oxidase. Species differences in the metabolism of Carbazeran in vitro correlate well with studies in vivo; these showed that following an oral dose to man and baboon, the compound was almost completely cleared via pre-systemic 4-hydroxylation, whereas in the dog, this metabolic route appeared unimportant.
Chronotropic and inotropic actions of amrinone, Carbazeran and isobutylmethyl xanthine: role of phosphodiesterase inhibition
Br J Pharmacol 1989 Sep;98(1):291-301.PMID:2478244DOI:10.1111/j.1476-5381.1989.tb16894.x.
1. The chronotropic and inotropic effects of amrinone, Carbazeran and 3-isobutyl-1-methyl xanthine (IBMX) were examined in isolated preparations of papillary muscle and right atria from rabbit heart. The effects of the drugs on cardiac phosphodiesterase and cyclic nucleotide content were also examined. 2. Amrinone (2.4 x 10(-4)M-2 x 10(-3) M), Carbazeran (9.1 x 10(-6) M-1.2 x 10(-3) M), and IBMX (1.8 x 10(-5) M-4.5 x 10(-4) M) produced concentration-dependent positive inotropic responses of papillary muscle preparations, the rank order of potency being Carbazeran = IBMX greater than amrinone. Sub-threshold positive inotropic concentrations of all three compounds potentiated the positive inotropic effects of isoprenaline; leftward shifts in the concentration-effect curves were 5 fold (IBMX), 11 fold (amrinone) and 46 fold (Carbazeran). 3. Amrinone and IBMX produced concentration-dependent positive chronotropic responses in isolated right atria and showed a similar rate selectivity to isoprenaline, but Carbazeran elicited a decrease in beating frequency. None of these drugs potentiated the positive chronotropic effects of isoprenaline. 4. Concentrations of amrinone, Carbazeran and IBMX that produced similar positive inotropic responses were associated with different increases in papillary muscle cyclic AMP and cyclic GMP concentrations. 5. All three compounds inhibited right atrial and ventricular phosphodiesterase, with amrinone being the least potent. There was, however, a marked difference between the IC50 and EC50 values for phosphodiesterase inhibition and positive inotropy. In contrast the positive chronotropic effects of amrinone and IBMX were observed in the same concentration ranges that produced phosphodiestrease inhibition. 6. The results indicate that amrinone possesses a similar rate/force selectivity to isoprenaline and IBMX. In contrast, Carbazeran exerts both positive inotropic and negative chronotropic effects. Phosphodiesterase inhibition and elevation of intracellular cyclic AMP concentration may be involved, at least in part, in the cardiac effects of these drugs.
Biotransformation of Carbazeran in guinea pig: effect of hydralazine pretreatment
Xenobiotica 1994 Jan;24(1):37-47.PMID:8165820DOI:10.3109/00498259409043219.
1. After administration of [14C]-carbazeran by oral gavage to guinea pigs, 48% of the dosed radioactivity was recovered in urine and 46% in faeces after 144 h. 2. The major urinary metabolite was identified by infrared spectroscopy and mass spectrometry as the O-glucuronide of O-desmethyl-4-oxocarbazeran, O-demethylation having taken place at the 6- or 7-position. The corresponding aglycone was identified as the major faecal metabolite. 3. A minor metabolite in urine was identified as the 4-oxo-4'-hydroxy derivative of Carbazeran. 4. In animals pretreated with hydralazine, an aldehyde oxidase inhibitor, less radioactivity was extracted in the urine and a significant decrease was observed in the levels of the major urinary metabolite. 5. These results show that aldehyde oxidase plays a key role in the metabolism of Carbazeran in guinea pig as it does in man. The similarity of man and guinea pig liver aldehyde oxidase has been observed previously in vitro.