Fuji Research Park, R&D Division, Kyowa Kirin, 1188, Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan; Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Fuji Research Park, R&D Division, Kyowa Kirin, 1188, Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan.
Bioorg Med Chem. 2019 Nov 15;27(22):115122. doi: 10.1016/j.bmc.2019.115122. Epub 2019 Sep 16.
We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPARγ ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.
我们之前发现二苯并氧杂环庚烯衍生物 1 是一种有效的 PPARγ 配体，由于其非噻唑烷二酮骨架，具有独特的结合模式。然而，虽然 1 对 MKN-45 胃癌细胞具有显著的聚集活性，这是 PPARγ 激活诱导的癌症分化诱导活性的指标，但我们认识到 1 代谢不稳定。在本研究中，我们确定了一个代谢上的弱点，并成功发现了代谢稳定性更好的 3-氟二苯并氧杂环庚烯衍生物 9。进一步优化提供了咪唑并[1,2-a]吡啶衍生物 17，与 9 相比，其对 MKN-45 胃癌细胞具有更强的聚集活性和优异的 PK 谱。化合物 17 在小鼠的 AsPC-1/AG1 胰腺肿瘤中表现出生长抑制作用。此外，即使在健康小鼠中以 200mg/kg 口服给药，红细胞压积（局部水肿的指标，PPARγ 配体的严重不良反应）的降低也是可以耐受的。
