Discovery of DS-6930, a potent selective PPARγ modulator. Part I: Lead identification. Issue 18 (1st October 2018)

• Record Type: Journal Article
• Authors: Shinozuka, Tsuyoshi; Tsukada, Tomoharu; Fujii, Kunihiko; Tokumaru, Eri; Shimada, Kousei; Onishi, Yoshiyuki; Matsui, Yumi; Wakimoto, Satoko; Kuroha, Masanori; Ogata, Tsuneaki; Araki, Kazushi; Ohsumi, Jun; Sawamura, Ryoko; Watanabe, Nobuaki; Yamamoto, Hideki; Fujimoto, Kazunori; Tani, Yoshiro; Mori, Makoto; Tanaka, Jun
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 18(2018)
• Page Start: 5079
• Page End: 5098
• Publication Date: 2018-10-01
• Subjects: PPARγ -- DS-6930 -- Benzimidazole; 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.2018.09.006
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The lead identification of a novel potent selective PPARγ agonist, DS-6930 is reported. To avoid PPARγ-related adverse effects, a partial agonist was designed to prevent the direct interaction with helix 12 of PPARγ-LBD. Because the TZD group is known to interact with helix 12, the TZD in efatutazone (CS-7017) was replaced to discover novel PPARγ intermediate partial agonist8i . The optimization of8i yielded13ac with high potency in vitro . Compound13ac exhibited robust plasma glucose lowering effects comparable to those of rosiglitazone (3 mg/kg) in Zucker diabetic fatty rats. Upon toxicological evaluation, compound13ac (300 mg/kg) induced hemodilution to a lower extent than rosiglitazone; however, 13ac elevated liver enzyme activities. X-ray crystallography revealed no direct interaction of13ac with helix 12, and the additional lipophilic interactions are also suggested to be related to the maximum transcriptional activity of13ac .