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

• Published in: Bioorganic & medicinal chemistry Vol. 33; p. 116019
• Main 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
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.03.2021; Elsevier
• Subjects: Antitumor effect; Biochemistry & Molecular Biology; Bladder cancer; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Fibroblast growth factor receptor 3; Life Sciences & Biomedicine; Molecular dynamics simulation; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure–activity relationships; X-ray crystal structure; X-ray crystal structure; Molecular dynamics simulation; Antitumor effect; Bladder cancer; Structure–activity relationships; Fibroblast growth factor receptor 3; PROLONGS SURVIVAL; SELECTIVE INHIBITOR; Structure-activity relationships br; EXPRESSION; DISCOVERY; FAMILY
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2021.116019

[Display omitted] 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.