BRAF inhibitors based on an imidazo[4,5]pyridin-2-one scaffold and a meta substituted middle ring

J Med Chem. 2010 Mar 11;53(5):1964-78. doi: 10.1021/jm901509a.

Arnaud Nourry ¹, Alfonso Zambon, Lawrence Davies, Ion Niculescu-Duvaz, Harmen P Dijkstra, Delphine Ménard, Catherine Gaulon, Dan Niculescu-Duvaz, Bart M J M Suijkerbuijk, Frank Friedlos, Helen A Manne, Ruth Kirk, Steven Whittaker, Richard Marais, Caroline J Springer

Affiliations

Affiliation

1 Cancer Research UK Centre of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.

PMID: 20148563 DOI: 10.1021/jm901509a

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 low-nanomolar 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.

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