Darapladib is one of the most potent Lp-PLA₂ (Lipoprotein-associated phospholipase A₂) inhibitor with an IC₅₀ of 0.25 nM. We demonstrate that a crucial step of Darapladib synthesis was not correctly described in the literature, leading to the production of wrong regioisomers. Moreover we show that the inhibitory activity is directly linked to the position on N1 since compounds bearing alkylation on different sites have potentially less interaction within the active site of Lp-PLA₂.

中文翻译：

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硫尿嘧啶烷基化的区域选择性：在优化Darapladib合成中的应用

Darapladib是最有效的Lp-PLA ₂（脂蛋白相关磷脂酶A ₂）抑制剂之一，IC ₅₀为0.25 nM。我们证明在文献中没有正确描述达拉帕地合成的关键步骤，从而导致错误的区域异构体的产生。此外，我们表明抑制活性直接与N1上的位置有关，因为在不同位点具有烷基化作用的化合物在Lp-PLA ₂的活性位点内可能具有较少的相互作用。