ONT-093
(Synonyms: OC 144-093; OC 144093) 目录号 : GC45784
A P-glycoprotein inhibitor
Cas No.:216227-54-2
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
ONT-093 is an orally bioavailable substituted diarylimidazole inhibitor of P-glycoprotein ATPase activity (IC50 = 0.16 μM).1 It reverses drug resistance to doxorubicin , vinblastine , and paclitaxel in human lymphoma, breast, ovarian, uterine, and colorectal cancer cell lines in vitro (EC50s = 9-38 nM). It is not cytotoxic to 15 normal, non-transformed, or tumor cell lines when used at concentrations up to 100 μM and exhibits weak cytostatic activity (average IC50 = >60 μM). ONT-093 (30 mg/kg) reverses paclitaxel drug resistance in an HCT15 human colon carcinoma mouse xenograft model.
|1. Newman, M.J., Rodarte, J.C., Benbatoul, K.D., et al. Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Res. 60(11), 2964-2972 (2000).
| Cas No. | 216227-54-2 | SDF | |
| 别名 | OC 144-093; OC 144093 | ||
| Canonical SMILES | CCOC/C=C/C1=CC=C(C2=NC(C3=CC=C(NC(C)C)C=C3)=C(C4=CC=C(NC(C)C)C=C4)N2)C=C1 | ||
| 分子式 | C32H38N4O | 分子量 | 494.7 |
| 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 | 2.0214 mL | 10.1071 mL | 20.2143 mL |
| 5 mM | 0.4043 mL | 2.0214 mL | 4.0429 mL |
| 10 mM | 0.2021 mL | 1.0107 mL | 2.0214 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。
ONT-093 (Ontogen)
Curr Opin Investig Drugs 2002 Nov;3(11):1666-71.PMID:12476971doi
Ontogen is developing ONT-093 (formerly OC-144-093), a P-glycoprotein pump inhibitor, for the potential reversal of multidrug resistance in patients undergoing cancer chemotherapy. The compound is also being evaluated for its potential enhancement of the oral bioavailability of drugs that are P-glycoprotein substrates requiring either high dosage forms or intravenous administration, and for the potential improvement of central nervous system penetration of P-glycoprotein substrate drugs.
Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093)
Cancer Chemother Pharmacol 2005 Jan;55(1):72-8.PMID:15316750DOI:10.1007/s00280-004-0864-4.
Objective: Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement of the oral uptake of docetaxel on combination with orally administered OC144-093, a potent P-gp inhibitor. Furthermore, the safety of combined treatment was determined and whether known functional genetic polymorphisms of the MDR1 gene could be associated with variability in docetaxel pharmacokinetics was also investigated. Patients and methods: A proof of concept study was carried out in 12 patients with advanced solid tumors. Patients were randomized to receive one course of 100 mg oral docetaxel combined with 500 mg OC144-093 followed 2 weeks later by a second i.v. course of docetaxel at a flat dose of 100 mg, without OC144-093, or vice versa. This was followed by standard i.v. docetaxel treatment if indicated. Results: The apparent relative oral bioavailability of docetaxel was 26+/-8%. Orally administered docetaxel combined with oral OC144-093 resulted in a Cmax of 415+/-255 ng ml(-1), an AUC0-infinity of 844+/-753 ng h ml(-1) and kel of 0.810+/-0.296 h(-1). These values differed significantly from those following i.v. administration of docetaxel, with a Cmax of 2124+/-1054 ng ml(-1), an AUC0-infinity of 2571+/-1598 ng h ml(-1) and a kel of 1.318+/-0.785 h(-1) (P=0.003, P=0.006, P=0.016). The study medication was well tolerated and most of the adverse events possibly or probably related to OC144-093 and docetaxel were of CTC grade 1 and 2. One patient had a homozygous 3435T/T mutation, which is associated with low intestinal P-gp expression, and two other patients had a homozygous mutation on exon 21. Conclusion: The relative apparent bioavailability of 26% was most likely caused by a significant effect of OC144-093 on the oral uptake of docetaxel. Large intrapatient and interpatient (pharmacokinetic) variation was found after oral as well as after i.v. administration of docetaxel. Higher plasma levels were observed after 100 mg i.v. docetaxel than after 100 mg oral docetaxel plus 500 mg oral OC144-093. The safety of the oral combination was good. More patients should be evaluated to determine the effect of P-gp single nucleotide polymorphisms on oral pharmacokinetic values of docetaxel.
A phase I pharmacokinetic study of the P-glycoprotein inhibitor, ONT-093, in combination with paclitaxel in patients with advanced cancer
Invest New Drugs 2005 Aug;23(4):311-5.PMID:16012790DOI:10.1007/s10637-005-1439-x.
Background: ONT-093 is an orally bioavailable inhibitor of P-glycoprotein (P-gp). In pre-clinical studies, ONT-093 could inhibit P-gp and reverse multidrug resistance at nM concentrations with no effect on paclitaxel pharmacokinetics. Phase I trials of ONT-093 in normal human volunteers showed no dose-limiting toxicities at serum concentrations associated with biologic activity achieved with doses ranging from 300 to 500 mg. Methods: Phase I pharmacokinetic trial of ONT-093 in doses from 300 to 500 mg administered before and after intravenous paclitaxel doses of 150 to 175 mg/m(2) repeated every 21 days. All patients received paclitaxel alone on cycle 1. Results: 18 patients were enrolled onto 4 dose levels. Toxicity of the combination included neutropenia, arthralgia, myalgia, and peripheral neuropathy. Four of 6 patients receiving 500 mg doses of ONT-093 and paclitaxel at 175 mg/m(2) (dose level 4) had higher-grade neutropenia with cycle 2, with 1 patient experiencing febrile neutropenia. Plasma pharmacokinetic parameters of paclitaxel were unchanged between cycle 1 and 2 for dose levels 1 to 3, but at dose level 4, 45-65% increases in paclitaxel AUC were observed in 4 of the 6 patients. Mean C(max) of ONT-093 was 9 microM (range 5-15 microM) which were 3- to 5-fold higher than in single agent studies of ONT-093. Conclusions: Doses of ONT-093 achieving serum concentrations associated with biological activity were well tolerated in combination with standard doses of paclitaxel. Toxicities of the combination in this schedule were mainly attributable to paclitaxel and dose-limiting toxicity was limited to febrile neutropenia. There was an apparent pharmacokinetic interaction between paclitaxel and ONT-093, possibly related in part to the excipient, Cremophor, present in the paclitaxel formulation.
P-glycoprotein activity and biological response
Toxicol Appl Pharmacol 2005 Sep 1;207(2 Suppl):257-60.PMID:16043202DOI:10.1016/j.taap.2005.03.027.
P-glycoprotein (P-gp) is a transmembrane drug efflux pump encoded by the MDR-1 gene in humans. Most likely P-gp protects organs against endogenous and exogenous toxins by extruding toxic compounds such as chemotherapeutics and other drugs. Many drugs are substrates for P-gp. Since P-gp is also expressed in the blood-brain barrier, P-gp substrates reach lower concentrations in the brain than in P-gp-negative tissues. Failure of response to chemotherapy of malignancies can be due to intrinsic or acquired drug resistance. Many tumors are multidrug resistant (MDR); resistant to several structurally unrelated chemotherapeutic agents. Several mechanisms are involved in MDR of which P-gp is studied most extensively. P-gp extrudes drugs out of tumor cells resulting in decreased intracellular drug concentrations, leading to the MDR phenotype. Furthermore, the MDR-1 gene exhibits several single nucleotide polymorphisms, some of which result in different transport capabilities. P-gp functionality and the effect of P-gp modulation on the pharmacokinetics of novel and established drugs can be studied in vivo by positron emission tomography (PET) using carbon-11 and fluorine-18-labeled P-gp substrates and modulators. PET may demonstrate the consequences of genetic differences on tissue pharmacokinetics. Inhibitors such as calcium-channel blockers (verapamil), cyclosporin A, ONT-093, and XR9576 can modulate the P-gp functionality. With PET the effect of P-gp modulation on the bioavailability of drugs can be investigated in humans in vivo. PET also allows the measurement of the efficacy of newly developed P-gp modulators.
Modulation of drug resistance transporters as a strategy for treating myelodysplastic syndrome
Best Pract Res Clin Haematol 2004 Dec;17(4):641-51.PMID:15494300DOI:10.1016/j.beha.2004.08.014.
Resistance to chemotherapy is an obstacle to the successful treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The failure of therapeutic treatment may be due to the development of multidrug resistance (MDR), mechanisms of which include upregulation of membrane-resident transporters which efflux chemotherapeutic drugs from tumor cells, and failure of the cancer cell to undergo apoptosis in response to chemotherapy. Membrane transporter-based drug efflux transporters have been extensively studied, and agents that block drug efflux have been found and investigated. Presence of P-glycoprotein (Pgp, MDR1, ABCB1), a member of the ATP-binding cassette (ABC) transporter family, has been reported to correlate with poor prognosis in AML and MDS. In MDS, Pgp expression increases as the disease progresses. Overexpression of other transporters, such as the multidrug resistance protein (MRP1, ABCC1), and the vault-associated transporter lung resistance protein have been shown as well in both MDS and AML, but their prognostic relevance is not clear. Recently, a novel ABC half-transporter, the breast cancer resistance protein (ABCG2) has been found in approximately 30% of AML cases, and may play a role in resistance to chemotherapy. In clinical trials in MDS, first-generation Pgp blockers, such as cyclosporin-A and verapamil, were minimally effective, non-specific, and toxic. However, another first-generation blocker, quinine, was used in MDS and may specifically benefit MDS patients overexpressing Pgp. A second-generation drug, the non-immunosuppressive cyclosporine analog valspodar (PSC833), was studied in AML and MDS, and was highly toxic, resulting in the need to reduce the dosage of the chemotherapeutic drugs as a result of valspodar reducing the clearance of the chemotherapeutic agents. Third-generation drugs, which are highly specific for Pgp and which seem to have only modest effects on drug clearance, include tariquidar, zosuquidar, laniquidar, and ONT-093. These are all in phase I/II trials and show promise for future treatment.