WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 202055
Description: ONT-093, also known as OC-144-093, is an orally bioavailable P-glycoprotein pump inhibitor, for the potential reversal of multidrug resistance in patients undergoing cancer chemotherapy. ONT-093 could inhibit P-gp and reverse multidrug resistance at nM concentrations with no effect on paclitaxel pharmacokinetics. OC144-093 is the least non-specifically toxic Pgp inhibitor described to date, with an average cytostatic IC50 of >60 microM in 15 cell types. OC144-093 may represent an ideal candidate for use in enhancement of AED blood-brain barrier penetration.
MedKoo Cat#: 202055
Chemical Formula: C32H38N4O
Exact Mass: 494.30456
Molecular Weight: 494.67
Elemental Analysis: C, 77.70; H, 7.74; N, 11.33; O, 3.23
Synonym: ONT-093; ONT 093; ONT093; OC-144-093; OC 144-093; OC144-093; OC-144093; OC 144093; OC144093.
IUPAC/Chemical Name: (E)-4,4'-(2-(4-(3-ethoxyprop-1-en-1-yl)phenyl)-1H-imidazole-4,5-diyl)bis(N-isopropylaniline)
InChi Key: RSJCLODJSVZNQA-BQYQJAHWSA-N
InChi Code: InChI=1S/C32H38N4O/c1-6-37-21-7-8-24-9-11-27(12-10-24)32-35-30(25-13-17-28(18-14-25)33-22(2)3)31(36-32)26-15-19-29(20-16-26)34-23(4)5/h7-20,22-23,33-34H,6,21H2,1-5H3,(H,35,36)/b8-7+
SMILES Code: CCOC/C=C/C1=CC=C(C2=NC(C3=CC=C(C=C3)NC(C)C)=C(C4=CC=C(C=C4)NC(C)C)N2)C=C1
Appearance: Light yellow to orange
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >5 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||ONT-093, also known as OC-144-093, is a P-glycoprotein pump inhibitor with an average cytostatic IC50 of >60 microM in 15 cell types.|
|In vitro activity:||OC144-093 was able to reverse resistance to all classes of P-gp substrates in a wide variety of tumor cell types with EC50s in the low nm range (Table 1 ). Complete reversal of MDR was typically seen with OC144-093 doses between 0.25 and 1.0 μm. Examples with cells expressing extremely high levels of P-gp as a result of drug selection (CEM/VLB1000), moderate levels of P-gp from gene transduction (MDA/LCC6MDR1), and low (intrinsic) levels of P-gp (HCT-15) are illustrated in detail in Fig. 2 . OC144-093 had no effect on doxorubicin or paclitaxel IC50s in non-P-gp-expressing CCRF-CEM and MDA/LCC6 cells, respectively, demonstrating the specificity of this compound for P-gp. OC144-093 retained full MDR reversal potency after incubation in human plasma, suggesting that protein binding-mediated inactivation will not be a problem in humans (data not shown). OC144-093 was able to reverse paclitaxel resistance in P-gp-expressing MCF-7/ADR cells by almost four orders of magnitude. OC144-093 had no effect on paclitaxel or etoposide IC50s in non-P-gp-expressing MCF-7 cells, further supporting the specificity of the compound for P-gp (data not shown). The HCT-15 human colon carcinoma cell line was derived from a patient not previously exposed to antitumor agents. OC144-093 was able to significantly reverse resistance to paclitaxel in this cell line in vitro (Fig. 2C ). Reference: Cancer Res. 2000 Jun 1;60(11):2964-72. https://pubmed.ncbi.nlm.nih.gov/10850444/|
|In vivo activity:||A standard i.p. P338 murine leukemia model of MDR was chosen for initial in vivo studies. OC144-093 (20 mg/kg) was found to almost completely reverse resistance to doxorubicin in this model. A dose-response for MDR reversal was observed at the lower doses (Table 4 ). On the bases of animal weight and mortality, no significant or reproducible enhancement of toxicity was observed when OC144-093 was combined with doxorubicin at the concentrations indicated. OC144-093 had no significant effect, by itself, on the survival of mice implanted with wild-type or MDR P388 ascites tumors (wild-type data not shown). In addition, OC144-093 did not enhance the life span of doxorubicin-treated mice implanted with wild-type P388 ascites tumors (Table 4) . The growth delay produced by paclitaxel and OC144-093 in the MDA/LCC6MDR1 xenografts was comparable with the growth delay produced by paclitaxel alone in MDA/LCC6 xenografts, suggesting complete reversal of MDR by OC144-093 (data not shown). Reference: Cancer Res. 2000 Jun 1;60(11):2964-72. https://pubmed.ncbi.nlm.nih.gov/10850444/|
The following data is based on the product molecular weight 494.67 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|Formulation protocol:||1. Newman MJ, Rodarte JC, Benbatoul KD, Romano SJ, Zhang C, Krane S, Moran EJ, Uyeda RT, Dixon R, Guns ES, Mayer LD. Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Res. 2000 Jun 1;60(11):2964-72. PMID: 10850444.|
|In vitro protocol:||1. Newman MJ, Rodarte JC, Benbatoul KD, Romano SJ, Zhang C, Krane S, Moran EJ, Uyeda RT, Dixon R, Guns ES, Mayer LD. Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Res. 2000 Jun 1;60(11):2964-72. PMID: 10850444.|
|In vivo protocol:||1. Newman MJ, Rodarte JC, Benbatoul KD, Romano SJ, Zhang C, Krane S, Moran EJ, Uyeda RT, Dixon R, Guns ES, Mayer LD. Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Res. 2000 Jun 1;60(11):2964-72. PMID: 10850444.|
1: Zhang N, Zhang Z, Wong IL, Wan S, Chow LM, Jiang T. 4,5-Di-substituted benzyl-imidazol-2-substituted amines as the structure template for the design and synthesis of reversal agents against P-gp-mediated multidrug resistance breast cancer cells. Eur J Med Chem. 2014 Aug 18;83:74-83. doi: 10.1016/j.ejmech.2014.06.016. Epub 2014 Jun 10. PubMed PMID: 24952376.
2: Modok S, Mellor HR, Callaghan R. Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer. Curr Opin Pharmacol. 2006 Aug;6(4):350-4. Epub 2006 May 11. Review. PubMed PMID: 16690355.
3: Vaalburg W, Hendrikse NH, Elsinga PH, Bart J, van Waarde A. P-glycoprotein activity and biological response. Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):257-60. Review. PubMed PMID: 16043202.
4: Chi KN, Chia SK, Dixon R, Newman MJ, Wacher VJ, Sikic B, Gelmon KA. 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. PubMed PMID: 16012790.
5: Ross DD. Modulation of drug resistance transporters as a strategy for treating myelodysplastic syndrome. Best Pract Res Clin Haematol. 2004 Dec;17(4):641-51. Review. PubMed PMID: 15494300.
6: Kuppens IE, Bosch TM, van Maanen MJ, Rosing H, Fitzpatrick A, Beijnen JH, Schellens JH. Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093). Cancer Chemother Pharmacol. 2005 Jan;55(1):72-8. Epub 2004 Aug 17. PubMed PMID: 15316750.
7: Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control. 2003 Mar-Apr;10(2):159-65. Review. PubMed PMID: 12712010.
8: Mistry P, Folkes A. ONT-093 (Ontogen). Curr Opin Investig Drugs. 2002 Nov;3(11):1666-71. Review. PubMed PMID: 12476971.
9: Guns ES, Denyssevych T, Dixon R, Bally MB, Mayer L. Drug interaction studies between paclitaxel (Taxol) and OC144-093--a new modulator of MDR in cancer chemotherapy. Eur J Drug Metab Pharmacokinet. 2002 Apr-Jun;27(2):119-26. PubMed PMID: 12064370.
10: Newman MJ, Dixon R, Toyonaga B. OC144-093, a novel P glycoprotein inhibitor for the enhancement of anti-epileptic therapy. Novartis Found Symp. 2002;243:213-26; discussion 226-30, 231-5. Review. PubMed PMID: 11990779.
11: Guns ES, Bullock PL, Reimer ML, Dixon R, Bally M, Mayer LD. Assessment of the involvement of CYP3A in the vitro metabolism of a new modulator of MDR in cancer chemotherapy, OC144-193, by human liver microsomes. Eur J Drug Metab Pharmacokinet. 2001 Oct-Dec;26(4):273-82. PubMed PMID: 11808870.
12: Kim KH. 3D-QSAR analysis of 2,4,5- and 2,3,4,5-substituted imidazoles as potent and nontoxic modulators of P-glycoprotein mediated MDR. Bioorg Med Chem. 2001 Jun;9(6):1517-23. PubMed PMID: 11408170.
13: Newman MJ, Rodarte JC, Benbatoul KD, Romano SJ, Zhang C, Krane S, Moran EJ, Uyeda RT, Dixon R, Guns ES, Mayer LD. Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Res. 2000 Jun 1;60(11):2964-72. PubMed PMID: 10850444.
ONT-093 (formerly OC-144-093) is a P-glycoprotein pump inhibitor, for the potential reversal of multidrug resistance in patients undergoing cancer chemotherapy. The compound was 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 [source: Prakash Mistry, Adrian Folkes. ONT-093 (Ontogen). Current opinion in investigational drugs (London, England : 2000). 2002 Nov;3(11): 1666-71 ]
A phase I pharmacokinetic study of ONT-093: 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. [source: Invest New Drugs. 2005 Aug;23(4):311-5.]