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

A Nourry; A Zambon; L Davies; I Niculescu-Duvaz; HP Dijkstra; D Ménard; C Gaulon; D Niculescu-Duvaz; BM Suijkerbuijk; F Friedlos; HA Manne; R Kirk; S. Whittaker; R.  Marais; CJ Springer

doi:10.1021/jm901509a

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

A Nourry, A Zambon, L Davies, I Niculescu-Duvaz, HP Dijkstra, D Ménard, C Gaulon, D Niculescu-Duvaz, BM Suijkerbuijk, F Friedlos, HA Manne, R Kirk, S. Whittaker, R. Marais, CJ Springer

Cancer Research UK Manchester Institute

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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.

Original language	English
Pages (from-to)	1964-1978
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	5
DOIs	https://doi.org/10.1021/jm901509a
Publication status	Published - 11 Feb 2010

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Nourry, A., Zambon, A., Davies, L., Niculescu-Duvaz, I., Dijkstra, HP., Ménard, D., Gaulon, C., Niculescu-Duvaz, D., Suijkerbuijk, BM., Friedlos, F., Manne, HA., Kirk, R., Whittaker, S., Marais, R., & Springer, CJ. (2010). BRAF inhibitors based on an imidazo[4,5]pyridin-2-one scaffold and a meta substituted middle ring. Journal of Medicinal Chemistry, 53(5), 1964-1978. https://doi.org/10.1021/jm901509a

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

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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Nourry, A, Zambon, A, Davies, L, Niculescu-Duvaz, I, Dijkstra, HP, Ménard, D, Gaulon, C, Niculescu-Duvaz, D, Suijkerbuijk, BM, Friedlos, F, Manne, HA, Kirk, R, Whittaker, S, Marais, R & Springer, CJ 2010, 'BRAF inhibitors based on an imidazo[4,5]pyridin-2-one scaffold and a meta substituted middle ring.', Journal of Medicinal Chemistry, vol. 53, no. 5, pp. 1964-1978. https://doi.org/10.1021/jm901509a

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AU - Zambon, A

AU - Davies, L

AU - Niculescu-Duvaz, I

AU - Dijkstra, HP

AU - Ménard, D

AU - Gaulon, C

AU - Niculescu-Duvaz, D

AU - Suijkerbuijk, BM

AU - Friedlos, F

AU - Manne, HA

AU - Kirk, R

AU - Whittaker, S.

AU - Marais, R.

AU - Springer, CJ

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SP - 1964

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IS - 5

ER -

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

Abstract

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