当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF).

Abstract：

:BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Niculescu-Duvaz D,Gaulon C,Dijkstra HP,Niculescu-Duvaz I,Zambon A,Ménard D,Suijkerbuijk BM,Nourry A,Davies L,Manne H,Friedlos F,Ogilvie L,Hedley D,Whittaker S,Kirk R,Gill A,Taylor RD,Raynaud FI,Moreno-Farre J,Marais

doi

10.1021/jm801509w

subject

Has Abstract

pub_date

2009-04-23 00:00:00

pages

2255-64

issue

8

eissn

0022-2623

issn

1520-4804

journal_volume

52

pub_type

杂志文章

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