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

Yamamoto, Keisuke; Tamura, Tomohiro; Nakamura, Rina; Hosoe, Shintaro; Matsubara, Masahiro; Nagata, Keiko; Kodaira, Hiroshi; Uemori, Takeshi; Takahashi, Yuichi; Suzuki, Michihiko; Saito, Jun-ichi; Ueno, Kimihisa; Shuto, Satoshi

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

Yamamoto, Keisuke; Tamura, Tomohiro; Nakamura, Rina et al.

Bioorganic & Medicinal Chemistry / Bioorganic and Medicinal Chemistry, 2019, 27(22), UNSP 115122

Permalink : https://hdl.handle.net/2115/83295

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アクセス権	open access
URI	https://hdl.handle.net/2115/83295
タイトル	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
著者	Yamamoto, Keisuke ; Tamura, Tomohiro ; Nakamura, Rina ; Hosoe, Shintaro ; Matsubara, Masahiro ; Nagata, Keiko ; Kodaira, Hiroshi ; Uemori, Takeshi ; Takahashi, Yuichi ; Suzuki, Michihiko ; Saito, Jun-ichi ; Ueno, Kimihisa ; Shuto, Satoshi
著者名 Yamamoto, Keisuke
著者名 Tamura, Tomohiro
著者名 Nakamura, Rina
著者名 Hosoe, Shintaro
著者名 Matsubara, Masahiro
著者名 Nagata, Keiko
著者名 Kodaira, Hiroshi
著者名 Uemori, Takeshi
著者名 Takahashi, Yuichi
著者名 Suzuki, Michihiko
著者名 Saito, Jun-ichi
著者名 Ueno, Kimihisa
e-Rad_Researcher 70241346 著者名 Shuto, Satoshi
言語	英語
発行日	2019-11-15
出版者	Elsevier
収録物名	Bioorganic & Medicinal Chemistry / Bioorganic and Medicinal Chemistry
巻(号)	27(22)
ページ	UNSP 115122
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
権利情報	© 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/
PISSN	0968-0896
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1016/j.bmc.2019.115122