F Hoffmann-La Roche Ltd, Pharma Research, CH-4070 Basel, Switzerland.
Bioorg Med Chem Lett. 2010 Feb 1;20(3):1106-8. doi: 10.1016/j.bmcl.2009.12.025. Epub 2009 Dec 6.
Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.
介绍了一类结构独特的 DPP-IV 抑制剂的合成和 SAR，这些抑制剂基于含有 S1 特异性口袋中（杂）芳基取代基的氨基苯并[a]喹啉。m-(氟甲基)-苯基衍生物（S,S,S）-2g 在 S1 口袋中具有最佳的适应性。然而，（S,S,S）-2i 带有一个更亲水的 5-甲基-吡啶-2-基取代基作为 S1 口袋的取代基，显示出优异的体内活性和良好的药物样特性。
