Ko 143

ABCG2:26 nM (EC50)

Ko143（10 mg/kg，p.o.）在小鼠中提高了SKF 104864A的口服可用性[2]。

在HEK G2细胞和鼠标G2细胞中，Ko143 (10 nM) 显著降低了MTX的IC50值。Ko143 (1-100 μM) 的代谢物并不抑制ABC转运蛋白的功能[1]。在经SKF 104864A选育的鼠标MEF3.8/T6400细胞和人IGROV1/T8细胞中，Ko143能够逆转药物抗性[2]。Ko143抑制了在Madin-Darby Canine Kidney (MDCK) 2-BCRP421CC（野生型）细胞和MDCK2-BCRP421AA（突变型）细胞中BCRP介导的ZD 4522运输[3]。

H2O:Insoluble;DMSO:90 mg/mL (191.66 mM)

Cells are plated at 400 or 1000/well in 96-well plates the night before the addition of drugs. A concentration series of the drug is applied along one plate axis and left for the duration of the assay. Plates are harvested after 4-5 days while untreated wells are still subconfluent. Relative cell proliferation is quantified with CyQuant or Sybr Green I fluorescent nucleic acid stains. Assays with human cell lines are performed in the presence of 0.1 μm PSC833 to inhibit confounding P-gp activity [2].

Oral toxicity of FTC analogs in mice is tested by mixing 50 mg/mL stocks in DMSO 1:1 with Tween 80 (polyoxyethylene sorbitan mono-oleate) and diluting with 5% w/v glucose such that the final volume administered by oral gavage is 10 μL/g of body weight. Pairs of mice are administered oral doses of 50 mg/kg Ko132, Ko134, Ko143, or vehicle under light methoxyflurane anesthesia. Final tests of 50 mg/kg Ko134 or Ko143 are performed on additional pairs of unanesthetized animals to observe any behavioral effects. Further, another pair of mice receive a higher dose of 100 mg/kg Ko134. For i.p. toxicity tests, the FTC analog stocks in DMSO are dispersed in at least 10 volumes of sterile corn oil such that the injected volume is 5 μL/g of body weight. After pilot tests at lower doses show no adverse effects, mice (4 per group) are administered vehicle or 10 mg/kg i.p. of Ko132, Ko134, or Ko143. The mice are observed continuously during the first hour after administration and then at increasing intervals for 2 weeks, after which they are sacrificed for histological examination of major organs and structures [2].