Chiral Sulfoxides as Metabolites of 2-Thioimidazole-Based p38α Mitogen-Activated Protein Kinase Inhibitors: Enantioselective Synthesis and Biological Evaluation
Chiral Sulfoxides as Metabolites of 2-Thioimidazole-Based p38α Mitogen-Activated Protein Kinase Inhibitors: Enantioselective Synthesis and Biological Evaluation
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DOI：
10.1021/jm101623p
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发表时间：
2011-05-12
影响因子：
7.3
通讯作者：
Laufer, Stefan A.
中科院分区：
文献类型：
--
作者：
Buehler, Stefanie;Goettert, Marcia;Laufer, Stefan A.
许多重要的药物都含有不对称的亚磺酰基结构，因此手性亚砜作为人体药物代谢产物的生物学评价对于开发安全有效的药物具有重要意义。不对称氧化是制备手性亚砜的最有吸引力的方法之一。在不同的手性配体的组合下，铁和钛催化的三取代和四取代的2-硫代咪唑的不对称氧化提供了相应的亚砜与对映体过量高达99%作为新的p38 α丝裂原活化蛋白激酶（p38 α MAPK）抑制剂。对映体纯的亚砜进行了评价，其对p38 α MAPK的抑制效力相比，各自的硫化物和亚砜外消旋体，并显示出在低纳摩尔范围内的IC（50）的酶的亲和力的差异。此外，检查了抑制肿瘤坏死因子-α（TNF-α）从人全血（HWB）释放的能力。一些吡啶基咪唑衍生物显示出优异的HWB活性，IC（50）低至52 nM。
A number of pharmaceutically important drugs contain asymmetric sulfinyl moieties, so the biological evaluation of chiral sulfoxides as human drug metabolites is important for the development of safe and effective pharmaceuticals. Asymmetric oxidation is one of the most attractive ways to prepare chiral sulfoxides. In combination with different chiral ligands, the iron- and titanium-catalyzed asymmetric oxidations of tri- and tetrasubstituted 2-thioimidazoles afford the corresponding sulfoxides with enantiomeric excesses up to 99% as novel p38a mitogen-activated protein kinase (p38 alpha MAPK) inhibitors. The enantiomerically pure sulfoxides were evaluated on their inhibitory potency against p38 alpha MAPK compared to the respective sulfides and sulfoxide racemates and showed differences in their affinities for the enzyme with IC(50) in the low nanomolar range. In addition, the ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) from human whole blood (HWB) was examined. Some pyridinylimidazole derivatives showed excellent HWB activity with IC(50) as low as 52 nM.