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

• Published in: Bioorganic & medicinal chemistry Vol. 27; no. 22; p. 115122
• Main 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
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.11.2019; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; GLUCOSE; GROWTH; LIVER; EFATUTAZONE; ADIPOGENESIS; COMBINATION; AGONIST; PACLITAXEL
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.115122

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. [Display omitted]