Synthesis and structure-activity relationships of pyrimidine derivatives as potent and orally active FGFR3 inhibitors with both increased systemic exposure and enhanced in vitro potency. (1st March 2021)

• Record Type: Journal Article
• Authors: Kuriwaki, Ikumi; Kameda, Minoru; Iikubo, Kazuhiko; Hisamichi, Hiroyuki; Kawamoto, Yuichiro; Kikuchi, Shigetoshi; Moritomo, Hiroyuki; Kondoh, Yutaka; Terasaka, Tadashi; Amano, Yasushi; Tateishi, Yukihiro; Echizen, Yuka; Iwai, Yoshinori; Noda, Atsushi; Tomiyama, Hiroshi; Nakazawa, Taisuke; Hirano, Masaaki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 33(2021)
• Publication Date: 2021-03-01
• Subjects: Fibroblast growth factor receptor 3 -- Bladder cancer -- Antitumor effect -- X-ray crystal structure -- Molecular dynamics simulation -- Structure–activity relationships; 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.2021.116019
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously. Specifically, reducing the molecular size of the substituent at the 4-position and replacing the linker of the 5-position in the pyrimidine scaffold resulted in an increase in systemic exposure. Furthermore, introduction of two fluorine atoms into the 3, 5-dimethoxyphenyl ring enhanced FGFR3 inhibitory activity. Molecular dynamics (MD) simulation of 20b suggested that the fluorine atom interacts with the main chain NH moiety of Asp635 via a hydrogen bond.