生物活性

• 描述Transcription factor hypoxia inducible factor-1 (HIF-1) is a master switch under hypoxia that upregulates the expression of multiple angiogenic proteins including stromal derived factor (SDF)-1, placental growth factor (PlGF), endothelin-1, VEGF and its receptor VEGFR-1. HIF-1 consists of a HIF-1α and a HIF-1β subunit. Ciclopirox and its olamine salt are family members of hydroxypyridone, which is a prolyl hydroxylase inhibitor and can stabilize HIF-1α predominantly in fibroblasts induced capillary sprouting in endothelial cells to increase angiogenesis^[4]. Moreover, ciclopirox is a potential drug for HBV. In a vitro study, HMSCs were stimulated with ciclopirox at dose of 10 μM for 24 h to perform subsequent gene expression analysis, suggesting that decrease of HIF-1α expression on gene level, whereas VEGF expression was upregulated by ciclopirox^[5]. In another vitro assay, a kind of truncated HBV core protein, cp149, was incubated with 0.1 - 10 μM ciclopirox and an anti-HBV core antibody was added for immunoblot analysis. The result showed that IC₅₀ value of ciclopirox was 445 ± 17 nM,, which indicated that ciclopirox potently affected intracellular HBV capsid assembly. In a vivo study, endothelial cells were cultured to observe sprouts of fibroblasts and only a few longer sprouts were observed. However, when ciclopirox at dose of 0.4 mM were introduced, an increase of sprout length ensued with the formation of a basal network and formation of anastomoses, indicating that ciclopirox induced secretion of VEGF^[4]. In another study, human liver-chimeric uPA/SCID mice were injected intravenously with HBV virion (5 × 10⁷ copies per mouse), and after 6 weeks the mice were treated daily with ciclopirox at dose of 5 mg/kg daily for 5 weeks. The data indicated that ciclopirox had lowered serum HBV DNA, HBeAg and serum ALT levels significantly. Furthermore, ciclopirox also significantly reduced HBV core protein levels in the liver. These evidences proved that ciclopirox is an effective HBV capsid assembly inhibitor^[6].
• 作用机制Hydrophobic residues L19, F23, F24, P25, Y118, F122, and W102, with extensive van der Waals interactions between ciclopirox and these residues form a binding pocket^[7]. And ciclopirox can mimic the effect of bipyridine, a well-known iron chelator and also an antifungal agent, upregulating the expression of the high-affinity iron permease gene FTR1 and the low-affinity iron permease gene FTR2, which are essential for iron metabolism^[8].

• 动物研究
  剂量	Rat: 1 mg/kg (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[3] Dose 1 mg/kg Administration p.o. Cmax 0.083 - 0.17 μg⁄ml T1/2 6.8 - 7.6 h