Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases
| Autor: | Morris Jeffrey James, Gordon S. Currie, Jason Grant Kettle, Claire Crafter, Clare Lane, Ken Page, Peter Ballard, Linette Ruston, Hannah Dry, Martin Pass, Andrew G. Leach, Ryan Greenwood, Matt Addie, Judit E. Debreczeni, Johnson Paul David, Barry R. Davies, Gillian M. Lamont, Donald J. Ogilvie, David Buttar, Philippa Dudley, Richard W. A. Luke, Stuart E. Pearson |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular medicine.drug_class hERG Administration Oral Carboxamide Pharmacology Inhibitory Concentration 50 Structure-Activity Relationship In vivo Cell Line Tumor Drug Discovery medicine Humans Structure–activity relationship Pyrroles Protein Kinase Inhibitors Protein kinase B biology Chemistry Kinase Xenograft Model Antitumor Assays Pyrimidines Biochemistry biology.protein Molecular Medicine Phosphorylation Female Proto-Oncogene Proteins c-akt Drug metabolism |
| Zdroj: | Journal of Medicinal Chemistry. 56:2059-2073 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm301762v |
| Popis: | Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model. |
| Databáze: | OpenAIRE |
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