Vaz Roy J, Li Yi, Chellaraj Vinolia, Reiling Stephan, Kuntzweiler Theresa, Yang Donglai, Shen Hong, Batchelor Joseph D, Zhang Ying, Chen Xin, McLean Larry R, Kosley Raymond
Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
Integrated Drug Discovery, Sanofi US, 153-2nd Ave., Waltham, MA 02451, USA.
Bioorg Med Chem Lett. 2018 Oct 15;28(19):3194-3196. doi: 10.1016/j.bmcl.2018.08.022. Epub 2018 Aug 20.
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，如何通过孕烷X受体（PXR）途径合理改善细胞色素P450 4/5（CYP3A4/5）的诱导作用。这些化合物最初通过在原代人肝细胞中进行的金标准诱导试验被证明可诱导CYP3A4/5。随后在PXR试验中对这些化合物进行测试，该试验与原代细胞中的试验结果相关性良好。此外，其中一种化合物与PXR结晶（pdb代码6DUP）。对该共晶体结构以及先前发表的PXR共晶体结构进行分析，得出了修饰思路。基于这些思路合成的化合物被证明不是CYP3A4/5诱导剂。所得化合物的mGluR2活性得以维持。
