Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014.
| Autor: | Pike KG; AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. kurt.pike@astrazeneca.com, Malagu K, Hummersone MG, Menear KA, Duggan HM, Gomez S, Martin NM, Ruston L, Pass SL, Pass M |
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| Jazyk: | angličtina |
| Zdroj: | Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Mar 01; Vol. 23 (5), pp. 1212-6. Date of Electronic Publication: 2013 Jan 18. |
| DOI: | 10.1016/j.bmcl.2013.01.019 |
| Abstrakt: | 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 IC(50), 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). (Copyright © 2013 Elsevier Ltd. All rights reserved.) |
| Databáze: | MEDLINE |
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