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Discovery of EBI-1051: A novel and orally efficacious MEK inhibitor with benzofuran scaffold.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2018 Feb 01; Vol. 26 (3), pp. 581-589. Date of Electronic Publication: 2017 Dec 20. - Publication Year :
- 2018
-
Abstract
- A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Benzofurans administration & dosage
Benzofurans pharmacokinetics
Benzofurans toxicity
Cell Line, Tumor
Cell Survival drug effects
Drug Evaluation, Preclinical
Enzyme Activation drug effects
Humans
Mice
Mice, Nude
Mitogen-Activated Protein Kinase Kinases metabolism
Neoplasms drug therapy
Neoplasms pathology
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors pharmacokinetics
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Transplantation, Heterologous
Benzofurans chemistry
Benzofurans pharmacology
Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 26
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29317148
- Full Text :
- https://doi.org/10.1016/j.bmc.2017.12.019