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P-gp/BCRP-IN-1

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P-gp/BCRP-IN-1 

P-gp/BCRP-IN-1 (compound 19) 是一种潜在的、相对安全的、口服有效的外排转运蛋白(P-gp 和 BCRP) 抑制剂。P-gp/BCRP-IN-1 通过抑制 P-gp 和 BCRP 的外排功能产生耐药性逆转，P-gp/BCRP-IN-1可克服紫杉醇的耐药性，提高紫杉醇的口服生物利用度。

P-gp/BCRP-IN-1

P-gp/BCRP-IN-1 Chemical Structure

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生物活性

P-gp/BCRP-IN-1 (compound 19) is a potential, relatively safe, orally active and efficient efflux transporter (P-gp and BCRP) inhibitor. P-gp/BCRP-IN-1 exerts resistance reversal by inhibiting the efflux function of P-gp and BCRP. P-gp/BCRP-IN-1 can overcome the resistance and improve the oral bioavailability of PTX (Paclitaxel)[1].

IC50 & Target

P-gp

 

体外研究
(In Vitro)

P-gp/BCRP-IN-1 (compound 19) (0-200 μM, 48 h) has a weak anti-proliferative activity against A549 cells, and shows low cytotoxicity to the K562 , K562/A02, MDCK-II, MDCK-II-BCRP cells[1].
P-gp/BCRP-IN-1 (48 h) exhibits the great reversal effect of resistance to both ADM (Adriamycin) and MX (Mitoxantrone) in K562/A02 cells and MDCK-II-BCRP cells, and increases the reversal activity of ADM (0-5 μM) and MX (0-20 μM) in a concentration-dependent manner[1].
P-gp/BCRP-IN-1 (0-5 μM, 4 h) increases drug accumulation and prevents efflux of P-gp and BCRP[1].
P-gp/BCRP-IN-1 (0-5 μM, 48 h) dose not affect the expression of P-gp as well as BCRP protein[1].
P-gp/BCRP-IN-1 (0-200 μM, 4 h) decreases the viability of Caco-2 cells, inhibits the intestinal P-gp-mediated efflux of PTX and increases its concentration in the intestinal cells, can enhance the absorption and bioavailability[1].
P-gp/BCRP-IN-1 prevents intracellular accumulation of anti-neoplastic drugs by impairing the function of P-gp and BCRP[1].

Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Proliferation Assay

Cell Line: A549 cells, chemo-sensitive cell lines (K562, MDCK-II), chemo-resistant cell lines (K562/A02, MDCK-II-BCRP)[1]
Concentration: 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.56 and 0 μM
Incubation Time: 24, 48 h
Result: Had a weak anti-proliferative activity against A549 cells, with an IC50 of 46.28 μM, and showed low cytotoxicity to the K562 , K562/A02, MDCK-II, MDCK-II-BCRP cells, with IC50 values of 72.81, 43.29, 87.69, 81.22 μM, respectively.

Cell Viability Assay

Cell Line: K562/A02 cells and MDCK-II-BCRP cells[1]
Concentration: 5 μM
Incubation Time: 48 h
Result: Increased the reversal activity of ADM (0-5 μM) and MX (0-20 μM) in a concentration-dependent manner, exhibited the great reversal effect of resistance to both ADM and MX in K562/A02 cells and MDCK-II-BCRP cells, with IC50 values (at 5 μM) of 2.41 and 18.43 μM, RF (reversal fold, at 5 μM) of 40.51 and 37.40, and EC50of 65.31 and 98.22 nM, respectively.

Western Blot Analysis

Cell Line: K562/A02 cells and MDCK-II-BCRP cells, K562 and MDCK-II cells.[1]
Concentration: 0, 0.5, 1, 5 μM
Incubation Time: 48 h
Result: Did not affect the expression of P-gp as well as BCRP protein, exerted resistance reversal without affecting the expression of P-gp as well as BCRP protein, but probably by inhibiting the efflux function of P-gp and BCRP.

Cell Viability Assay

Cell Line: Caco-2 cells[1]
Concentration: 1.25, 5, 10, 20, 30, 50, 100, 200 μM
Incubation Time: 4 h
Result: Decreased the viability of Caco-2 cells to less than 20% at concentrations of 30 and 50 μM respectively, significantly decreased the Papp (apparent permeability coefficient) value, inhibited the intestinal P-gp-mediated efflux of PTX and increased its concentration in the intestinal cells, which could eventually enhance the absorption and bioavailability of the orally administered drug.

体内研究
(In Vivo)

P-gp/BCRP-IN-1 (compound 19) (Male SD rats; 5 mg/kg PTX (IV), 20 mg/kg PTX (PO), 20 mg/kg PTX and 10 mg/kg compound 19 (PO); once) increases the bioavailability of PTX when PTX is given orally[1].
Pharmacokinetic Parameters of P-gp/BCRP-IN-1 in male SD rats[1].

PTX (5 mg/kg) PTX (20 mg/kg) PTX (20 mg/kg) with 19 (10 mg/kg)
Routemax (h) IV PO PO
AUC0-t (ng*h/mL) 1734.95 ± 244.28 610.89 ± 45.62 3131.51 ± 63.17
Cmax (ng/mL) 925.86 ± 31.39 112.09 ± 25.46 652.31 ± 41.93
Tmax (h) 0.44 ± 0.05 2.00 ± 0.03 2.51 ± 0.19
T1/2 (h) 0.12 ± 0.03 1.35 ± 0.05 1.68 ± 0.15
Vd/F (L) 5.06 ± 0.09 67.38 ± 12.54 16.04 ± 0.08
CL/F (L/h) 2.88 ± 0.14 32.74 ± 5.42 6.18 ± 0.36
F (%) 100 8.80 45.1

Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Male SD rats (n = 15, three groups)[1]
Dosage: 5 mg/kg PTX (IV); 20 mg/kg PTX (PO); 20 mg/kg PTX with 10 mg/kg compound 19 (PO)
Administration: IV, PO, once (Pharmacokinetic Analysis)
Result: Increased the bioavailability of PTX when PTX was given orally.

分子量

488.97

Formula

C27H25ClN4O3
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献

  • [1]. Shi W, Zhang P, Zou F, et al. Exploration of novel phthalazinone derivatives as potential efflux transporter inhibitors for reversing multidrug resistance and improving the oral absorption of paclitaxel. Eur J Med Chem. 2022;233:114231.

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