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Updated: Apr 28, 2026
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15N CPMG Relaxation Dispersion for the Investigation of Protein Conformational Dynamics on the µs-ms Timescale
Published on: April 19, 2021
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Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning.
Toshihiro Aoki1, Ikumi Hyohdoh1, Noriyuki Furuichi1
1Research Division, Chugai Pharmaceutical Co., Ltd. , 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
ACS Medicinal Chemistry Letters
|June 6, 2014
Summary
Nitrogen substitution in aromatic compounds enhances solubility and metabolic stability. This led to the selection of compound 1 (CH5126766/RO5126766) for clinical trials in solid cancers.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Organic Synthesis
Background:
- Aromatic compounds are crucial in drug development.
- Improving solubility and metabolic stability are key challenges.
- Targeting cancer pathways like Raf/MEK is a significant area of research.
Purpose of the Study:
- To investigate the effects of nitrogen substitution on aromatic compounds.
- To enhance solubility and metabolic stability of lead compounds.
- To identify novel inhibitors of cancer cell growth and Raf/MEK signaling.
Main Methods:
- Nitrogen scanning was applied to aromatic ring structures.
- Compounds were evaluated for solubility and metabolic stability.
- Interactions with on- and off-target proteins (Raf/MEK, CYPs, hERG) were assessed.
- Inhibitory activity against HCT116 cell growth was measured.
Main Results:
- Nitrogen substitution improved solubility and metabolic stability.
- Most derivatives showed weaker interactions with target and off-target proteins.
- Compound 1 (CH5126766/RO5126766) retained inhibitory activity against HCT116 cell growth and Raf/MEK.
- Compound 1 was selected as a clinical candidate.
Conclusions:
- Nitrogen substitution is a viable strategy for optimizing drug properties.
- Compound 1 demonstrates potential as a therapeutic agent for solid cancers.
- A phase I clinical trial for compound 1 is currently underway.
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