This work describes the rational amelioration of Cytochrome P450 4/5 (CYP3A4/5) induction through the Pregnane-X Receptor (PXR) pathway in a series of compounds that modulate the metabotropic glutamate Receptor 2 (mGluR2) via an allosteric mechanism. The compounds were initially shown to induce CYP3A4/5 via the gold-standard induction assay measured in primary human hepatocytes. This was followed up by testing the compounds in a PXR assay which correlated well with the assay in primary cells. Further, one of the compounds was crystallized with PXR (pdb code 6DUP). Analysis of this co-crystal structure, together with previously published PXR co-crystal structures, lead to modification ideas. The compounds synthesized based on these ideas were shown not to be CYP3A4/5 inducers. The mGluR2 activity of the resulting compounds was maintained.

这项工作描述了通过一系列通过变构机制调节代谢型谷氨酸受体2（mGluR2）的化合物，通过Pregnane-X受体（PXR）途径合理改善了细胞色素P450 4/5（CYP3A4 / 5）的诱导作用。最初通过在原代人肝细胞中测得的金标准诱导试验证明了该化合物诱导CYP3A4 / 5。随后在PXR分析中测试化合物，该化合物与原代细胞中的分析密切相关。此外，用PXR（pdb代码6DUP）使一种化合物结晶。对这种共晶体结构以及先前发布的PXR共晶体结构的分析导致了修改思路。根据这些想法合成的化合物显示不是CYP3A4 / 5诱导剂。维持所得化合物的mGluR2活性。