We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo[4,5]pyridin-2-one scaffold and a substituted urea linker. Here, we present a new series of BRAF inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of lownanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series. © 2010 American Chemical Society.
BRAF inhibitors based on an imidazo[4,5]pyridin-2-one scaffold and a meta substituted middle ring / Nourry, Arnaud; Zambon, Alfonso; Davies, Lawrence; Niculescu Duvaz, Ion; Dijkstra, Harmen P.; Ménard, Delphine; Gaulon, Catherine; Niculescu Duvaz, Dan; Suijkerbuijk, Bart M. J. M.; Manne, Frank Friedlos Helen A.; Kirk, Ruth; Whittaker, Steven; Marais, Richard; Springer, Caroline J.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 53:5(2010), pp. 1964-1978. [10.1021/jm901509a]
BRAF inhibitors based on an imidazo[4,5]pyridin-2-one scaffold and a meta substituted middle ring
ZAMBON, Alfonso;
2010
Abstract
We recently reported on the development of a novel series of BRAF inhibitors based on a tripartite A-B-C system characterized by a para-substituted central aromatic core connected to an imidazo[4,5]pyridin-2-one scaffold and a substituted urea linker. Here, we present a new series of BRAF inhibitors in which the central phenyl ring connects to the hinge binder and substrate pocket of BRAF with a meta-substitution pattern. The optimization of this new scaffold led to the development of lownanomolar inhibitors that permits the use of a wider range of linkers and terminal C rings while enhancing the selectivity for the BRAF enzyme in comparison to the para series. © 2010 American Chemical Society.
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