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首页> 外文期刊>Chemical research in toxicology >Bioactivation of isothiazoles: minimizing the risk of potential toxicity in drug discovery.
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Bioactivation of isothiazoles: minimizing the risk of potential toxicity in drug discovery.

机译：异噻唑的生物激活：将药物发现中潜在毒性的风险降至最低。

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Compound 1, (7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)m ethyl)-1,5-naphthyridin-4-amine) is a potent, selective inhibitor of c-Met (mesenchymal-epithelial transition factor), a receptor tyrosine kinase that is often deregulated in cancer. Compound 1 displayed desirable pharmacokinetic properties in multiple preclinical species. Glutathione trapping studies in liver microsomes resulted in the NADPH-dependent formation of a glutathione conjugate. Compound 1 also exhibited very high in vitro NADPH-dependent covalent binding to microsomal proteins. Species differences in covalent binding were observed, with the highest binding in rats, mice, and monkeys (1100-1300 pmol/mg/h), followed by dogs (400 pmol/mg/h) and humans (144 pmol/mg/h). This covalent binding to protein was abolished by coincubation with glutathione. Together, these in vitro data suggest that covalent binding and glutathione conjugation proceed via bioactivation to a chemically reactive intermediate. The cytochrome (CYP) P450 enzymes responsible for this bioactivation were identified as cytochrome P450 3A4, 1A2, and 2D6 in human and cytochrome P450 2A2, 3A1, and 3A2 in rats. The glutathione metabolite was detected in the bile of rats and mice, thus demonstrating bioactivation occurring in vivo. Efforts to elucidate the structure of the glutathione adduct led to the isolation and characterization of the metabolite by NMR and mass spectrometry. The analytical data confirmed conclusively that the glutathione conjugation was on the 4-C position of the isothiazole ring. Such P450-mediated bioactivation of an isothiazole or thiazole group has not been previously reported. We propose a mechanism of bioactivation via sulfur oxidation followed by glutathione attack at the 4-position with subsequent loss of water resulting in the formation of the glutathione conjugate. Efforts to reduce bioactivation without compromising potency and pharmacokinetics were undertaken in order to minimize the potential risk of toxicity. Because of the exemplary pharmacokinetic/pharmacodynamic (PK/PD) properties of the isothiazole group, initial attempts were focused on introducing alternative metabolic soft spots into the molecule. These efforts resulted in the discovery of 7-(2-methoxyethoxy)-N-((6-(3-methyl-5-isothiazolyl)[1,2,4]triazolo[4,3-b]pyridazi n-3-yl)methyl)-1,5-naphthyridin-4-amine (compound 2), with the major metabolic transformation occurring on the naphthyridine ring alkoxy substituent. However, a glutathione conjugate of compound 2 was produced in vitro and in vivo in a manner similar to that observed for compound 1. Furthermore, the covalent binding was high across species (360, 300, 529, 208, and 98 pmol/mg/h in rats, mice, dogs, monkeys, and humans, respectively), but coincubation with glutathione reduced the extent of covalent binding. The second viable alternative in reducing bioactivation involved replacing the isothiazole ring with bioisosteric heterocycles. Replacement of the isothiazole ring with an isoxazole or a pyrazole reduced the bioactivation while retaining the desirable PK/PD characteristics of compounds 1 and 2.
机译：化合物1，（7-甲氧基-N-（（（6-（3-甲基异噻唑-5-基）-[1,2,4]三唑并[4,3-b]哒嗪-3-基）甲基）-1 ，5-萘啶-4-胺）是一种有效的选择性c-Met抑制剂（间质-上皮转化因子），一种受体酪氨酸激酶，在癌症中通常被解除调节。化合物1在多种临床前物种中显示出所需的药代动力学性质。肝微粒体中的谷胱甘肽捕获研究导致了NADPH依赖性的谷胱甘肽结合物形成。化合物1还表现出非常高的体外NADPH依赖性共价结合至微粒体蛋白。观察到共价结合的物种差异，其中大鼠，小鼠和猴子的结合最高（1100-1300 pmol / mg / h），其次是狗（400 pmol / mg / h）和人（144 pmol / mg / h） ）。通过与谷胱甘肽共孵育消除了与蛋白质的共价结合。总之，这些体外数据表明，共价结合和谷胱甘肽结合是通过生物活化作用发生化学反应的中间体而进行的。负责此生物激活的细胞色素（CYP）P450酶被鉴定为人中的细胞色素P450 3A4、1A2和2D6，在大鼠中被鉴定为细胞色素P450 2A2、3A1和3A2。在大鼠和小鼠的胆汁中检测到谷胱甘肽代谢物，从而证明了体内发生了生物活化。阐明谷胱甘肽加合物的结构的努力导致了通过NMR和质谱法对代谢产物的分离和表征。分析数据最终证实，谷胱甘肽结合在异噻唑环的4-C位置上。以前尚未报道过P450介导的异噻唑或噻唑基团的生物活化。我们提出了一种通过硫氧化的生物活化机制，然后在4位上发生谷胱甘肽攻击，随后损失水分导致谷胱甘肽缀合物形成的机制。为了使潜在的毒性风险最小化，已进行了努力以减少生物活化而不损害效能和药代动力学。由于异噻唑基团的示例性药代动力学/药效学（PK / PD）特性，最初的尝试集中在将替代性代谢软点引入分子中。这些努力导致发现7-（2-甲氧基乙氧基）-N-（（6-（3-甲基-5-异噻唑基）[1,2,4]三唑[4,3-b]吡啶并n-3- （甲基）-1，5-萘啶-4-胺（化合物2），主要的代谢转化发生在萘啶环烷氧基取代基上。但是，化合物2的谷胱甘肽共轭物以与化合物1相似的方式在体外和体内产生。此外，物种间的共价结合率很高（360、300、529、208和98 pmol / mg / mg分别在大鼠，小鼠，狗，猴子和人类中h），但是与谷胱甘肽共孵育降低了共价结合的程度。减少生物活化的第二种可行替代方法包括用生物等位杂环取代异噻唑环。用异恶唑或吡唑取代异噻唑环可降低生物活性，同时保留化合物1和2所需的PK / PD特性。

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