title: Optimization of tetrahydronaphthalene inhibitors of Raf with selectivity over hERG.
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.
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Shih-Chung
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Adhikari
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Roushan
authors.initials: R
authors.lastname: Afroze
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Brewer
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Emily F
authors.initials: EF
authors.lastname: Calderwood
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Jouhara
authors.initials: J
authors.lastname: Chouitar
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Dylan B
authors.initials: DB
authors.lastname: England
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Fisher
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Galvin
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Gaulin
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Greenspan
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Harrison
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Langston
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Ma
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Menon
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Mizutani
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Rezaei
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Dong Mei
authors.initials: DM
authors.lastname: Zhang
authors.affiliation: Takeda Pharmaceuticals International Co. 40 Landsdowne Street, Cambridge, MA 02139, United States.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Gould
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D016296:Mutagenesis; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014183:Transplantation, Heterologous
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D047428:Protein Kinase Inhibitors; D013764:Tetrahydronaphthalenes; D048493:Proto-Oncogene Proteins B-raf
keywords: B-Raf; B-Raf inhibitor; hERG