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 Inhib
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- 作者：Matt Addie ; Peter Ballard ; David Buttar ; Claire Crafter ; Gordon Currie ; Barry R. Davies ; Judit Debreczeni ; Hannah Dry ; Philippa Dudley ; Ryan Greenwood ; Paul D. Johnson ; Jason G. Kettle ; Clare Lane ; Gillian Lamont ; Andrew Leach ; Richard W. A. Luke ; Jeff Morris ; Donald Ogilvie ; Ken Page ; Martin Pass ; Stuart Pearson ; Linette Ruston
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：March 14, 2013
- 年：2013
- 卷：56
- 期：5
- 页码：2059-2073
- 全文大小：579K
- 年卷期：v.56,no.5(March 14, 2013)
- ISSN：1520-4804
文摘
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.