Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Bioorg Med Chem Lett. 2010 May 1;20(9):2938-41. doi: 10.1016/j.bmcl.2010.03.017. Epub 2010 Mar 7.
For the purpose of reducing the strong CYP3A4 inhibitory potency of diamide prodrug 4, cyclic prodrugs of tricyclic-based FBPase inhibitors were synthesized. Extensive SAR studies led to the discovery of pyridine-containing cyclic prodrug 20, which strongly inhibited glucose production in monkey hepatocytes and also showed weak CYP3A4 inhibitory potency.
为了降低二酰胺前药 4 的强 CYP3A4 抑制效力，合成了基于三环的 FBPase 抑制剂的环状前药。广泛的 SAR 研究导致发现了含有吡啶的环状前药 20，它强烈抑制了猴肝细胞中的葡萄糖产生，并且对 CYP3A4 也具有较弱的抑制效力。
