Optimization of tetrahydronaphthalene inhibitors of Raf with selectivity over hERG

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1156-60. doi: 10.1016/j.bmcl.2016.01.049.

Shih-Chung Huang ¹, Sharmila Adhikari ¹, Roushan Afroze ¹, Katherine Brewer ¹, Emily F Calderwood ¹, Jouhara Chouitar ¹, Dylan B England ¹, Craig Fisher ¹, Katherine M Galvin ¹, Jeffery Gaulin ¹, Paul D Greenspan ¹, Sean J Harrison ¹, Mi-Sook Kim ¹, Steven P Langston ¹, Li-Ting Ma ¹, Saurabh Menon ¹, Hirotake Mizutani ¹, Mansoureh Rezaei ¹, Michael D Smith ¹, Dong Mei Zhang ¹, Alexandra E Gould ¹

Affiliations

Affiliation

1 Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.

PMID: 26804230 DOI: 10.1016/j.bmcl.2016.01.049

Abstract

Investigations of a biaryl ether scaffold identified tetrahydronaphthalene Raf inhibitors with good in vivo activity; however these compounds had affinity toward the hERG Potassium Channel. Herein we describe our work to eliminate this hERG activity via alteration of the substituents on the benzoic amide functionality. The resulting compounds have improved selectivity against the hERG channel, good pharmacokinetic properties and potently inhibit the Raf pathway in vivo.

Keywords

B-Raf; B-Raf inhibitor; hERG.

Name
Email *

	Sorry, but the email address you supplied was invalid.