Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014

• Published in: Bioorganic & medicinal chemistry letters 2013-03, Vol.23 (5), p.1212-1216
• Main Authors: Pike, Kurt G., Malagu, Karine, Hummersone, Marc G., Menear, Keith A., Duggan, Heather M.E., Gomez, Sylvie, Martin, Niall M.B., Ruston, Linette, Pass, Sarah L., Pass, Martin
• Format: Article
• Language: English
• Subjects: AZD2014; AZD8055; Cell Growth Processes - drug effects; Cells, Cultured; Hepatocytes - drug effects; Hepatocytes - enzymology; Hepatocytes - metabolism; Humans; Inhibitor; inhibitory concentration 50; Kinase; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; metabolism; Morpholines - pharmacology; mTOR; Multiprotein Complexes - antagonists & inhibitors; Protein Kinase Inhibitors - pharmacology; solubility; TOR Serine-Threonine Kinases - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.01.019

The optimization of a novel series of highly potent and selective dual inhibitors of mTORC1 and mTORC2 is described culminating in the discovery of clinical candidates AZD8055 (14) and AZD2014 (21). The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC50, led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).