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Discovery of 2-arylamino-4-(1-methyl-3-isopropylsulfonyl-4-pyrazol-amino)pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Sep 01; Vol. 25 (17), pp. 3738-43. Date of Electronic Publication: 2015 Jun 16. - Publication Year :
- 2015
-
Abstract
- A new series of 2,4-diamino pyrimidine derivatives with a sulfone-substituted pyrazole right side-chain were discovered as potent anaplastic lymphoma kinase inhibitors. Structure-activity relationship of the left side-chain on phenyl substitutions were explored which delivered many potent ALK inhibitors. Among them, 29a showed favorable pharmacokinetic profiles in rats and dogs together with significant antitumor efficacy in EML4-ALK fusion xenograft model.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Biological Availability
Chemistry Techniques, Synthetic
Dogs
Drug Design
Drug Discovery
Humans
Mice
Molecular Targeted Therapy
Oncogene Proteins, Fusion genetics
Pyrimidines pharmacology
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases genetics
Structure-Activity Relationship
Xenograft Model Antitumor Assays methods
Antineoplastic Agents pharmacology
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Pyrimidines chemistry
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 25
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 26130408
- Full Text :
- https://doi.org/10.1016/j.bmcl.2015.06.021