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.
Bioorg Med Chem
; 33: 116019, 2021 03 01.
Article
em En
| MEDLINE
| ID: mdl-33486159
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.
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
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Neoplasias da Bexiga Urinária
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Receptor Tipo 3 de Fator de Crescimento de Fibroblastos
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Antineoplásicos
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article