Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity

Zhijian Zhao; Ronald G Robinson; Stanley F Barnett; Deborah Defeo-Jones; Raymond E Jones; George D Hartman; Hans E Huber; Mark E Duggan; Craig W Lindsley

doi:10.1016/j.bmcl.2007.11.015

Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity

Bioorg Med Chem Lett. 2008 Jan 1;18(1):49-53. doi: 10.1016/j.bmcl.2007.11.015. Epub 2007 Nov 13.

Authors

Zhijian Zhao¹, Ronald G Robinson, Stanley F Barnett, Deborah Defeo-Jones, Raymond E Jones, George D Hartman, Hans E Huber, Mark E Duggan, Craig W Lindsley

Affiliation

¹ Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck & Co., PO Box 4, West Point, PA 19486, USA. zhijian_zhao@merck.com

PMID: 18054229
DOI: 10.1016/j.bmcl.2007.11.015

Abstract

This letter describes the development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved aqueous solubility (approximately 18 mg/mL) that translates into enhanced cell activity and caspase-3 induction.

MeSH terms

Caspase 3 / metabolism
Cell Line, Tumor
Enzyme Activation
HT29 Cells
Humans
Kinetics
Phosphorylation
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Quinoxalines / chemical synthesis
Quinoxalines / chemistry*
Quinoxalines / pharmacology*
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / chemistry*
Serine Proteinase Inhibitors / pharmacology*
Solubility
Water / chemistry

Substances

Quinoxalines
Serine Proteinase Inhibitors
Water
Proto-Oncogene Proteins c-akt
Caspase 3