基于 4-氨基-6-甲基-1,3,5-三嗪磺酰胺骨架的双 PI3K/mTOR 抑制剂的合成与构效关系研究。
Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold.
机构信息
Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
出版信息
Bioorg Med Chem Lett. 2012 Sep 1;22(17):5714-20. doi: 10.1016/j.bmcl.2012.06.078. Epub 2012 Jul 3.
Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC(50) and exhibited good oral bioavailability in rats (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC(50)=193 nM (91 ng/mL).
磷酸肌醇 3-激酶（PI3K）是肿瘤学中的一个重要靶点，因为在多种肿瘤中，PI3K/Akt 信号通路的失调。我们合成了一系列 4-氨基-6-甲基-1,3,5-三嗪磺酰胺，并将其评估为 PI3K 抑制剂。本文描述了这些化合物的合成、体外生物活性、药代动力学和体内药效学特征。从这项研究中发现，最有前途的化合物（化合物 3j）是一种泛 I 类 PI3K 抑制剂，在酶测定中对哺乳动物雷帕霉素靶蛋白（mTOR）的选择性超过 10 倍。在 U87 MG 细胞测定中，测定 Akt 的磷酸化，化合物 3j 显示出低双位数纳摩尔的 IC（50），并且在大鼠中具有良好的口服生物利用度（F（oral）=63%）。化合物 3j 在 U87 肿瘤药效学模型中也表现出剂量依赖性降低 Akt 的磷酸化，其血浆 EC（50）为 193 nM（91ng/mL）。
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