Literature DB >> 24900832

Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning.

Toshihiro Aoki1, Ikumi Hyohdoh1, Noriyuki Furuichi1, Sawako Ozawa1, Fumio Watanabe1, Masayuki Matsushita1, Masahiro Sakaitani1, Kenji Morikami2, Kenji Takanashi1, Naoki Harada1, Yasushi Tomii1, Koji Shiraki2, Kentaro Furumoto2, Mitsuyasu Tabo2, Kiyoshi Yoshinari1, Kazutomo Ori1, Yuko Aoki1, Nobuo Shimma1, Hitoshi Iikura3.   

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.

Entities:  

Keywords:  CH5126766; MEK; Nitrogen scan; RO5126766; Raf; kinase inhibitor

Year:  2014        PMID： 24900832      PMCID： PMC4027752          DOI： 10.1021/ml400379x

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  26 in total

Review 1.  Medicinal chemistry of hERG optimizations: Highlights and hang-ups.

Authors:  Craig Jamieson; Elizabeth M Moir; Zoran Rankovic; Grant Wishart
Journal:  J Med Chem       Date:  2006-08-24       Impact factor: 7.446

Review 2.  High throughput solubility measurement in drug discovery and development.

Authors:  Jochem Alsenz; Manfred Kansy
Journal:  Adv Drug Deliv Rev       Date:  2007-05-29       Impact factor: 15.470

3.  Strong conformational preferences of heteroaromatic ethers and electron pair repulsion.

Authors:  Rong-Jie Chein; E J Corey
Journal:  Org Lett       Date:  2010-01-01       Impact factor: 6.005

Review 4.  Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety.

Authors:  Nicholas A Meanwell
Journal:  Chem Res Toxicol       Date:  2011-07-26       Impact factor: 3.739

5.  Quinolinone-based agonists of S1P₁: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

Authors:  Lewis D Pennington; Michael D Croghan; Kelvin K C Sham; Alexander J Pickrell; Paul E Harrington; Michael J Frohn; Brian A Lanman; Anthony B Reed; Matthew R Lee; Han Xu; Michele McElvain; Yang Xu; Xuxia Zhang; Michael Fiorino; Michelle Horner; Henry G Morrison; Heather A Arnett; Christopher Fotsch; Andrew S Tasker; Min Wong; Victor J Cee
Journal:  Bioorg Med Chem Lett       Date:  2011-11-04       Impact factor: 2.823

6.  Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties.

Authors:  Ikumi Hyohdoh; Noriyuki Furuichi; Toshihiro Aoki; Yoshiko Itezono; Haruyoshi Shirai; Sawako Ozawa; Fumio Watanabe; Masayuki Matsushita; Masahiro Sakaitani; Pil-Su Ho; Kenji Takanashi; Naoki Harada; Yasushi Tomii; Kiyoshi Yoshinari; Kazutomo Ori; Mitsuyasu Tabo; Yuko Aoki; Nobuo Shimma; Hitoshi Iikura
Journal:  ACS Med Chem Lett       Date:  2013-09-22       Impact factor: 4.345

7.  Discovery of a highly potent, selective, and bioavailable soluble epoxide hydrolase inhibitor with excellent ex vivo target engagement.

Authors:  Hong C Shen; Fa-Xiang Ding; Siyi Wang; Qiaolin Deng; Xiaoping Zhang; Yuli Chen; Gaochao Zhou; Suoyu Xu; Hsuan-Shen Chen; Xinchun Tong; Vincent Tong; Kaushik Mitra; Sanjeev Kumar; Christine Tsai; Andra S Stevenson; Lee-Yuh Pai; Magdalena Alonso-Galicia; Xiaoli Chen; Stephen M Soisson; Sophie Roy; Bei Zhang; James R Tata; Joel P Berger; Steven L Colletti
Journal:  J Med Chem       Date:  2009-08-27       Impact factor: 7.446

8.  Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.

Authors:  Allen J Duplantier; Stacey L Becker; Michael J Bohanon; Kris A Borzilleri; Boris A Chrunyk; James T Downs; Lain-Yen Hu; Ayman El-Kattan; Larry C James; Shenping Liu; Jiemin Lu; Noha Maklad; Mahmoud N Mansour; Scot Mente; Mary A Piotrowski; Subas M Sakya; Susan Sheehan; Stefanus J Steyn; Christine A Strick; Victoria A Williams; Lei Zhang
Journal:  J Med Chem       Date:  2009-06-11       Impact factor: 7.446

9.  Characterization of type II ligands in CYP2C9 and CYP3A4.

Authors:  Marie M Ahlström; Ismael Zamora
Journal:  J Med Chem       Date:  2008-03-01       Impact factor: 7.446

10.  Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity.

Authors:  Nobuya Ishii; Naoki Harada; Eric W Joseph; Kazuhiro Ohara; Takaaki Miura; Hiroshi Sakamoto; Yutaka Matsuda; Yasushi Tomii; Yukako Tachibana-Kondo; Hitoshi Iikura; Toshihiro Aoki; Nobuo Shimma; Mikio Arisawa; Yoshihiro Sowa; Poulikos I Poulikakos; Neal Rosen; Yuko Aoki; Toshiyuki Sakai
Journal:  Cancer Res       Date:  2013-05-10       Impact factor: 12.701
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  3 in total

1.  Novel Nitric Oxide Donors of Phenylsulfonylfuroxan and 3-Benzyl Coumarin Derivatives as Potent Antitumor Agents.

Authors:  Yalan Guo; Yujie Wang; Haihong Li; Ke Wang; Qi Wan; Jia Li; Yubo Zhou; Ying Chen
Journal:  ACS Med Chem Lett       Date:  2018-04-20       Impact factor: 4.345

2.  From methylene bridged diindole to carbonyl linked benzimidazoleindole: Development of potent and metabolically stable PCSK9 modulators.

Authors:  Haibo Xie; Ka Yang; Gabrielle N Winston-McPherson; Donnie S Stapleton; Mark P Keller; Alan D Attie; Kerry A Smith; Weiping Tang
Journal:  Eur J Med Chem       Date:  2020-08-04       Impact factor: 6.514

Review 3.  Innovation in the discovery of the HIV-1 attachment inhibitor temsavir and its phosphonooxymethyl prodrug fostemsavir.

Authors:  Tao Wang; John F Kadow; Nicholas A Meanwell
Journal:  Med Chem Res       Date:  2021-09-28       Impact factor: 1.965
  3 in total

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