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. Issue 22 (15th November 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 22(2019)
• Publication Date: 2019-11-15
• Subjects: Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115122
• Languages: English
• ISSNs: 0968-0896

Abstract

Abstract: We previously identified dibenzooxepine derivative1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative9 with better metabolic stability. Further optimization provided imidazo[1, 2- a ]pyridine derivative17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with9 . Compound17 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. Graphical abstract: Unlabelled Image