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.
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THN-fused C3-spirooxindoles should possess good druglikeness because THN and spirooxindole derivatives are privileged drug-like architectures.
“We started with THN54, 55, 56, 57, 58, 59, 60, 61 and spirooxindole derivatives62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72 because they are privileged drug-like architectures, so the resulting THN-fused C3-spirooxindoles should possess good druglikeness (Fig. 2C).”
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- Authors
- Huang, S.-C., Adhikari, S., Afroze, R., Brewer, K., Calderwood, E. F., Chouitar, J., England, D. B., Fisher, C., Galvin, K. M., Gaulin, J., Greenspan, P. D., Harrison, S. J., Kim, M.-S., Langston, S. P., Ma, L.-T., Menon, S., Mizutani, H., Rezaei, M., Smith, M. D., Zhang, D. M., & Gould, A. E.
- Corresponding author
- Huang, Shih-Chung
- ORCID
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 26
- Issue
- 4
- Pages
- 1156-1160
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2251905544
- Cited by
- 10
- References
- 14
- Citations by year
- 2025: 2 · 2024: 2 · 2021: 1 · 2020: 2 · 2019: 2 · 2017: 1
- FWCI
- 0.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- Raf kinase inhibitor, tetralin, hERG, biaryl ethers, structure-activity optimization, selectivity, pharmacokinetics
- MeSH terms
- Animals, Humans, Male, Neoplasms, Protein Binding, Structure-Activity Relationship, Tetrahydronaphthalenes, Transplantation, Heterologous, Mutagenesis, Rats, Sprague-Dawley, Inhibitory Concentration 50, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Mice, Rats, Ether-A-Go-Go Potassium Channels
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