硫脲嘧啶烷基化的区域选择性：在达普拉地合成优化中的应用。
Regioselectivity of thiouracil alkylation: Application to optimization of Darapladib synthesis.
作者信息
Guibbal Florian, Bénard Sébastien, Patché Jessica, Meneyrol Vincent, Couprie Joël, Yong-Sang Jennyfer, Meilhac Olivier, Jestin Emmanuelle
机构信息
Université de La Réunion, INSERM, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), Saint-Denis de La Réunion, France.
Radiochimie et imagerie du petit animal (RIPA), CYclotron Réunion Océan Indien CYROI, 2 rue Maxime Rivière, 97490 Sainte-Clotilde, France.
出版信息
Bioorg Med Chem Lett. 2018 Feb 15;28(4):787-792. doi: 10.1016/j.bmcl.2017.12.052. Epub 2017 Dec 24.
Darapladib is one of the most potent Lp-PLA (Lipoprotein-associated phospholipase A) inhibitor with an IC 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-PLA.
达普拉迪布是最有效的脂蛋白相关磷脂酶A（Lp-PLA）抑制剂之一，其半数抑制浓度为0.25纳摩尔。我们证明，文献中未正确描述达普拉迪布合成的关键步骤，导致生成了错误的区域异构体。此外，我们表明抑制活性与N1位直接相关，因为在不同位点进行烷基化的化合物在Lp-PLA活性位点内的相互作用可能较少。
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