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
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.]
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.