کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10158441 | 1666526 | 2018 | 29 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
TP0463518, a novel inhibitor for hypoxia-inducible factor prolyl hydroxylases, increases erythropoietin in rodents and monkeys with a good pharmacokinetics-pharmacodynamics correlation
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب سلولی و مولکولی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: TP0463518, a novel inhibitor for hypoxia-inducible factor prolyl hydroxylases, increases erythropoietin in rodents and monkeys with a good pharmacokinetics-pharmacodynamics correlation TP0463518, a novel inhibitor for hypoxia-inducible factor prolyl hydroxylases, increases erythropoietin in rodents and monkeys with a good pharmacokinetics-pharmacodynamics correlation](/preview/png/10158441.png)
چکیده انگلیسی
Hypoxia-inducible factor prolyl hydroxylases (PHDs) inhibitor stabilizes hypoxia inducible factor alpha, which increases erythropoietin (EPO) expression via the hypoxia response element. Therefore, PHDs inhibitors have been developed as novel therapeutic agents for anemia. Here, we characterize the in vitro and in vivo pharmacological profiles of TP0463518, 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]â4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid, a novel potent PHDs inhibitor. TP0463518 competitively inhibited human PHD2 with a Ki value of 5.3â¯nM. TP0463518 also inhibited human PHD1/3 with IC50 values of 18 and 63â¯nM as well as monkey PHD2 with an IC50 value of 22â¯nM. In normal mice and rats, TP0463518 significantly increased the serum EPO levels at doses of 5 and 20â¯mg/kg, respectively. The correlation factors for serum EPO and the serum TP0463518 levels were 0.95 in mice and 0.92 in rats. TP0463518 also increased the serum EPO level in 5/6 nephrectomized chronic kidney disease model rats at a dose of 10â¯mg/kg, with a correlation factor for serum EPO and the serum TP0463518 levels of 0.82. Finally, the effect of TP0463518 in monkeys was investigated. TP0463518 was promptly removed with a half-life of 5.2â¯h and increased the area under the curve (AUC) of EPO at a dose of 5â¯mg/kg. The EPO and TP0463518 levels were also correlated. These results suggest that TP0463518 induces endogenous EPO with a strong pharmacokinetic-pharmacodynamic correlation and may contribute to desirable hemoglobin control in patients with renal anemia.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmacology - Volume 838, 5 November 2018, Pages 138-144
Journal: European Journal of Pharmacology - Volume 838, 5 November 2018, Pages 138-144
نویسندگان
Sota Kato, Noriko Takayama, Hiroki Takano, Hiroko Koretsune, Chie Koizumi, Ei-ichi Kunioka, Saeko Uchida, Teisuke Takahashi, Koji Yamamoto,