Liarozole
(Synonyms: 利阿唑,R75251) 目录号 : GC61971
A CYP26A1 inhibitor
Cas No.:115575-11-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Liarozole is an inhibitor of the cytochrome P450 (CYP) isoform CYP26A1 (IC50 = 2.1 ?M), an enzyme involved in the metabolism of all-trans retinoic acid .1 It also inhibits the production of estradiol induced by follicle-stimulating hormone (FSH) in rat granulosa cells and testosterone and androstenedione production induced by human chorionic gonadotropin (hCG) in rat testicular cells (IC50s = 0.4, 2.3, and 0.7 ?M, respectively).2 Liarozole enhances the antiproliferative activity of all-trans retinoic acid in MCF-7 breast cancer cells.3 It decreases plasma levels of retinoic acid in rats in a dose-dependent manner.4 Liarozole (5 and 20 mg/kg) decreases estradiol undecylate-induced vaginal keratinization in ovariectomized rats.
1.Thatcher, J.E., Buttrick, B., Shaffer, S.A., et al.Substrate specificity and ligand interactions of CYP26A1, the human liver retinoic acid hydroxylaseMol. Pharmacol.80(2)228-239(2011) 2.Bruynseels, J., De Coster, R., Rooy, P.V., et al.R 75251, a new inhibitor of steroid biosynthesisProstate16(4)345-357(1990) 3.Wouters, W., van Dun, J., Dillen, A., et al.Effects of liarozole, a new antitumoral compound, on retinoic acid-induced inhibition of cell growth and on retinoic acid metabolism in MCF-7 human breast cancer cellsCancer Res.52(10)2841-2846(1992) 4.Van Wauwe, J., Van Nyen, G., Coene, M.C., et al.Liarozole, an inhibitor of retinoic acid metabolism, exerts retinoid-mimetic effects in vivoJ. Pharmacol. Exp. Ther.261(2)773-779(1992)
| Cas No. | 115575-11-6 | SDF | |
| 别名 | 利阿唑,R75251 | ||
| Canonical SMILES | ClC1=CC(C(C2=CC=C3N=CNC3=C2)N4C=CN=C4)=CC=C1 | ||
| 分子式 | C17H13ClN4 | 分子量 | 308.76 |
| 溶解度 | >20mg/ml in DMSO | 储存条件 | 4°C, protect from light |
| 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 | 3.2388 mL | 16.1938 mL | 32.3876 mL |
| 5 mM | 0.6478 mL | 3.2388 mL | 6.4775 mL |
| 10 mM | 0.3239 mL | 1.6194 mL | 3.2388 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。
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Liarozole
Drugs Aging 1996 Dec;9(6):478-84; discussion 485.PMID:8972247DOI:10.2165/00002512-199609060-00010.
Liarozole prevents the catabolism of retinoic acid via inhibition of 4-hydroxylase and exhibits retinoid-sparing and retinoid-mimetic effects in vivo. Liarozole is also a potent inhibitor of estrogen (via inhibition of aromatase) and testicular androgen synthesis (inhibition of 17, 20-lyase). Although testosterone levels decrease in vivo after single dose administration of Liarozole, testosterone levels normalise as a result of pituitary feedback after multiple doses. Liarozole reduced the tumour size of androgen-dependent and -independent prostatic carcinomas in animal models. Liarozole also demonstrated chemopreventive activity in vivo. In phase I and II trials in patients with relapsed prostate cancer, Liarozole achieved a complete response (assessed using prostate specific antigen levels) in 4% and a partial response in 26% of patients. Cutaneous adverse events, similar to those associated with excess levels of retinoic acid, were the most frequently reported events associated with Liarozole.
Experimental studies with Liarozole (R 75,251): an antitumoral agent which inhibits retinoic acid breakdown
J Steroid Biochem Mol Biol 1992 Sep;43(1-3):197-201.PMID:1525060DOI:10.1016/0960-0760(92)90208-z.
Liarozole reduced tumor growth in the androgen-dependent Dunning-G and the androgen-independent Dunning MatLu rat prostate carcinoma models as well as in patients with metastatic prostate cancer who had relapsed after orchiectomy. In vitro, Liarozole did not have cytostatic properties, as measured by cell proliferation in breast MCF-7 and prostate DU145 and LNCaP carcinoma cell lines. It did not alter the metabolism of labeled testosterone i.e. the 5 alpha-reductase in cultured rat prostatic cells. In mouse F9 teratocarcinoma cells Liarozole did not show any retinoid-like properties but enhanced the plasminogen activator production induced by retinoic acid. Furthermore, Liarozole and retinoic acid similarly reduced the growth of the androgen-dependent Dunning-G tumor in nude mice and inhibited tumor promotion elicited by phorbol ester in mouse skin. These data have raised the hypothesis that the antitumoral properties of Liarozole may be related to inhibition of retinoic acid degradation, catalyzed by a P-450-dependent enzyme that is blocked by the drug.
Ketoconazole and Liarozole in the treatment of advanced prostatic cancer
Cancer 1993 Feb 1;71(3 Suppl):1068-73.PMID:8428329DOI:10.1002/1097-0142(19930201)71:3+<1068::aid-cncr2820711427>3.0.co;2-5.
Background: Ketoconazole, an imidazole derivative, is an orally active antifungal agent. In high doses (400 mg three times a day), it inhibits the biosynthesis of testicular and adrenal androgens and may therefore be useful for the treatment of hormone dependent diseases such as advanced prostatic cancer. Similarly, a new imidazole derivative, Liarozole, was recently found to interfere with testicular and adrenal steroid biosynthesis in animals and healthy volunteers. Methods: The therapeutic and endocrine effects of ketoconazole and Liarozole in patients with disseminated prostatic cancer are discussed, including data from the literature and personal experience. Results: Using high-dose ketoconazole, medical castration with the expected clinical response was achieved easily in previously untreated patients in all clinical series (personal data include seven patients). In patients with prostatic cancer who had relapses after castration, few objective remissions were achieved. By contrast, long-lasting subjective remissions, especially pain relief, were seen in more than half of the patients (personal data include 20 patients). Gastrointestinal intolerance, which was the main side effect, severely limits the routine use of the drug. Recently, the authors studied the effect of Liarozole on adrenal steroid production in castrated patients whose disease was progressive after first-line treatment. Unlike ketoconazole therapy, adrenal androgen and cortisol levels were not modified. A Phase I-II trial was then done in 44 patients with metastatic prostatic cancer in clinical relapse. In patients with measurable disease, objective responses, including tumoral volume reduction, occurred in approximatively 30%. A prostate specific antigen reduction of 50% or more was noted in approximatively 50% of patients. Pain relief occurred in most patients. Mucocutaneous side effects were observed in most patients--dryness of the skin and onychomalacia. Raised tissue retinoic acid levels suggested a possible pathway by which this drug might exert its cytotoxic effects. Conclusions: Ketoconazole in high doses is effective in first-line and second-line therapy for advanced prostatic cancer, but gastrointestinal side effects limit its routine use. Liarozole is a new imidazole that is also effective in second-line therapy for prostatic cancer and has fewer side effects. Unlike ketoconazole, its effect is not mediated by inhibition of steroid biosynthesis.
Liarozole inhibits transforming growth factor-β3--mediated extracellular matrix formation in human three-dimensional leiomyoma cultures
Fertil Steril 2014 Jul;102(1):272-281.e2.PMID:24825427DOI:10.1016/j.fertnstert.2014.03.042.
Objective: To investigate the impact of Liarozole on transforming growth factor-β3 (TGF-β3) expression, TGF-β3 controlled profibrotic cytokines, and extracellular matrix formation in a three-dimensional (3D) leiomyoma model system. Design: Molecular and immunohistochemical analysis in a cell line evaluated in a three-dimensional culture. Setting: Laboratory study. Patient(s): None. Intervention(s): Treatment of leiomyoma and myometrial cells with Liarozole and TGF-β3 in a three-dimensional culture system. Main outcome measure(s): Quantitative real-time reverse-transcriptase polymerase chain reaction and Western blotting to assess fold gene and protein expression of TGF-β3 and TGF-β3 regulated fibrotic cytokines: collagen 1A1 (COL1A1), fibronectin, and versican before and after treatment with Liarozole, and confirmatory immunohistochemical stains of treated three-dimensional cultures. Result(s): Both TGF-β3 gene and protein expression were elevated in leiomyoma cells compared with myometrium in two-dimensional and 3D cultures. Treatment with Liarozole decreased TGF-β3 gene and protein expression. Extracellular matrix components versican, COL1A1, and fibronectin were also decreased by Liarozole treatment in 3D cultures. Treatment of 3D cultures with TGF-β3 increased gene expression and protein production of COL1A1, fibronectin, and versican. Conclusion(s): Liarozole decreased TGF-β3 and TGF-β3-mediated extracellular matrix expression in a 3D uterine leiomyoma culture system.
Liarozole, an inhibitor of retinoic acid metabolism, exerts retinoid-mimetic effects in vivo
J Pharmacol Exp Ther 1992 May;261(2):773-9.PMID:1374473doi
Liarozole is an imidazole-containing compound that inhibits the cytochrome P-450-dependent metabolism of all-trans-retinoic acid (RA). In vitro, Liarozole (IC50, 2.2 microM) suppressed the P-450-mediated conversion of RA to more polar metabolites by hamster liver microsomes. In vivo, it enhanced the plasma level of RA from mostly undetectable values (less than 0.5 ng/ml) in control rats to 1.4 +/- 0.1 and 2.9 +/- 0.1 ng/ml in animals treated p.o. with 5 and 20 mg/kg of Liarozole, respectively. Moreover, Liarozole possessed antikeratinizing activity: when dosed subchronically (5-20 mg/kg, once daily for 3 days) to ovariectomized rats, the compound reversed the vaginal keratinization induced in these animals by estrogenic stimulation. Dose response experiments indicated that the antikeratinizating effect of Liarozole was as potent as that of RA. One-dimensional electrophoresis and immunoblotting of extracted vaginal epithelia showed that Liarozole shared with RA the ability to inhibit the synthesis of high molecular weight (57-60 kDa) keratin proteins, and to enhance the expression of the 45 to 47 kDa keratin polypeptides. Furthermore, we found that antikeratinizing doses of Liarozole doubled the RA concentration in the vagina of ovariectomized rats: the mean amount of RA extracted from 200 mg of vaginal tissue was increased from 1.1 +/- 0.1 ng in vehicle-treated animals to 2.2 +/- 0.2 and 2.6 +/- 0.2 ng after treatment with 5 and 20 mg/kg of Liarozole, respectively. These findings indicate that Liarozole, an inhibitor of RA metabolism and RA produce similar morphologic and biochemical effects on the differentiation process of rat vaginal epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)