Selection of hydroxypyridin-4-ones for the treatment of iron overload using in vitro and in vivo models.
Selection of hydroxypyridin-4-ones for the treatment of iron overload using in vitro and in vivo models.
复制标题
使用体外和体内模型选择羟基吡啶-4-酮治疗铁过载。
作者：
E. Huehns;J. Porter;R. Hider
羟基吡啶-4-酮组的铁螯合剂显示出作为通过口服途径治疗铁过载的潜在化合物的前景。在寻找最适合长期临床使用的化合物时，必须在动员最大量的铁的愿望和使此类化合物的潜在毒性最小化的愿望之间取得平衡。在这篇文章中，我们回顾的方法，我们已经用来评估的羟基吡啶酮具有最适合进一步发展的性能之前，在man. The的多样性的一些密切相关的化合物取代的环上的氮的临床试验，使我们能够研究的性质的螯合剂负责细胞动员铁（III），以及那些可能有助于其毒性。原代肝细胞培养模型有助于研究其铁结合常数的贡献，以及其相对脂溶性对细胞铁动员和毒性的至关重要性。在小鼠中进行的类似研究证实，影响细胞铁释放的因素也控制整个动物的铁排泄。此外，我们已经证明，这组化合物的急性毒性与可用铁池的大小密切相关。（250字处删节）
The hydroxypyridin-4-one group of iron chelators show promise as potential compounds for the treatment of iron overload by the oral route. In the search for the compounds best suited for long term clinical use, a balance has to be struck between the desire to mobilise the maximum amount of iron and the wish to minimise the potential toxicity of such compounds. In this article we review the approach we have used to evaluate which of the hydroxypyridinones have the properties best suited for further development prior to clinical trials in man. The diversity of a number of closely related compounds substituted on the ring nitrogen have allowed us to study the properties of chelators responsible for cellular mobilisation of iron(III), as well as those which may contribute to their toxicity. The primary hepatocyte culture model has facilitated the investigation of the contribution of their iron binding constant, as well as the critical importance of their relative lipid solubility to both cellular iron mobilisation and toxicity. Similarly studies in mice have confirmed that the factors affecting cellular iron release also control iron excretion in whole animals. Further we have demonstrated that the acute toxicity of this group of compounds is closely linked to the size of the available iron pool.(ABSTRACT TRUNCATED AT 250 WORDS)