The design and synthesis of potent and cell-active allosteric dual Akt 1 and 2 inhibitors devoid of hERG activity

Tony Siu; Yiwei Li; Johnny Nagasawa; Jun Liang; Lida Tehrani; Peter Chua; Raymond E Jones; Deborah Defeo-Jones; Stanley F Barnett; Ronald G Robinson

doi:10.1016/j.bmcl.2008.05.084

The design and synthesis of potent and cell-active allosteric dual Akt 1 and 2 inhibitors devoid of hERG activity

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4191-4. doi: 10.1016/j.bmcl.2008.05.084. Epub 2008 May 24.

Authors

Tony Siu¹, Yiwei Li, Johnny Nagasawa, Jun Liang, Lida Tehrani, Peter Chua, Raymond E Jones, Deborah Defeo-Jones, Stanley F Barnett, Ronald G Robinson

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., 3535 General Atomics Court, San Diego, CA 92129, USA. address: tony_siu@merck.com

PMID: 18550373
DOI: 10.1016/j.bmcl.2008.05.084

Abstract

This letter details the attenuation of hERG in a class of Akt inhibitors through heteroatom insertions into aromatic rings. The development of a cell-active dual Akt 1 and 2 inhibitors devoid of hERG activity is discussed using structure-activity relationships.

MeSH terms

Allosteric Regulation
Allosteric Site
Chemistry, Pharmaceutical / methods
Drug Design
ERG1 Potassium Channel
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Ether-A-Go-Go Potassium Channels / chemistry*
Ether-A-Go-Go Potassium Channels / metabolism
Humans
Inhibitory Concentration 50
Models, Chemical
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Structure-Activity Relationship

Substances

ERG1 Potassium Channel
Enzyme Inhibitors
Ether-A-Go-Go Potassium Channels
KCNH2 protein, human
Proto-Oncogene Proteins c-akt