| Title: | Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold |
| Authors: | Yamamoto, Keisuke Browse this author |
| Tamura, Tomohiro Browse this author |
| Nakamura, Rina Browse this author |
| Hosoe, Shintaro Browse this author |
| Matsubara, Masahiro Browse this author |
| Nagata, Keiko Browse this author |
| Kodaira, Hiroshi Browse this author |
| Uemori, Takeshi Browse this author |
| Takahashi, Yuichi Browse this author |
| Suzuki, Michihiko Browse this author |
| Saito, Jun-ichi Browse this author |
| Ueno, Kimihisa Browse this author |
| Shuto, Satoshi Browse this author →KAKEN DB |
| Issue Date: | 15-Nov-2019 |
| Publisher: | Elsevier |
| Journal Title: | Bioorganic & Medicinal Chemistry / Bioorganic and Medicinal Chemistry |
| Volume: | 27 |
| Issue: | 22 |
| Start Page: | UNSP 115122 |
| Publisher DOI: | 10.1016/j.bmc.2019.115122 |
| Abstract: | We previously identified dibenzooxepine derivative 1 as a potent PPAR. 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 PPAR. 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-alpha]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 PPAR gamma ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice. |
| Rights: | © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/83295 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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