TrkA kinase inhibitors from a library of modified and isosteric Staurosporine aglycone
| Autor: | John P. Mallamo, Shi X. Yang, Thelma S. Angeles, Rabindranath Tripathy |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Isostere Stereochemistry Clinical Biochemistry Carbazoles Molecular Conformation Pharmaceutical Science Antineoplastic Agents Stereoisomerism Biochemistry Rats Sprague-Dawley Small Molecule Libraries Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Animals Structure–activity relationship Pyrroles Receptor trkA Protein Kinase Inhibitors Molecular Biology Indole test biology Organic Chemistry Diastereomer Neoplasms Experimental Staurosporine Xenograft Model Antitumor Assays Rats Aglycone nervous system chemistry Enzyme inhibitor biology.protein Molecular Medicine Bioisostere |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 18:3551-3555 |
| ISSN: | 0960-894X |
| Popis: | An immobilized Staurosporine aglycone isostere where one of the indole nitrogen atoms was replaced by carbon has been sequentially functionalized to generate compounds inhibiting TrkA kinase. In the first phase, initial screening of a library of C13-hydroxymethyl-7-oxo-indenopyrrolocarbazoles resulted in several potent compounds, one of which was further optimized to generate the corresponding carbamates on solid phase. Some of the major carbamate diastereomers were found to be several-fold more potent than their alcohol parents. Synthesis, SAR analysis, kinase selectivity, and anti-tumor properties of a TrkA inhibitor (12a) are discussed. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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