title: Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning.
abstract: Substituting a carbon atom with a nitrogen atom (nitrogen substitution) on an aromatic ring in our leads 11a and 13g by applying nitrogen scanning afforded a set of compounds that improved not only the solubility but also the metabolic stability. The impact after nitrogen substitution on interactions between a derivative and its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel) was also detected, most of them contributing to weaker interactions. After identifying the positions that kept inhibitory activity on HCT116 cell growth and Raf/MEK, compound 1 (CH5126766/RO5126766) was selected as a clinical compound. A phase I clinical trial is ongoing for solid cancers.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Hyohdoh
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Furuichi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Ozawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Watanabe
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakaitani
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Takanashi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tomii
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Shiraki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Furumoto
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Tabo
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshinari
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Kazutomo
authors.initials: K
authors.lastname: Ori
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shimma
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan ; Research Division, Chugai Pharmaceutical Co., Ltd. , 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iikura
keywords: CH5126766; MEK; Nitrogen scan; RO5126766; Raf; kinase inhibitor