Allosteric inhibitors of Akt1 and Akt2: discovery of [1,2,4]triazolo[3,4-f][1,6]naphthyridines with potent and balanced activity

Yiwei Li; Jun Liang; Tony Siu; Essa Hu; Michael A Rossi; Stanley F Barnett; Deborah Defeo-Jones; Raymond E Jones; Ronald G Robinson; Karen Leander; Hans E Huber; Sachin Mittal; Nicholas Cosford; Peppi Prasit

doi:10.1016/j.bmcl.2008.12.017

Allosteric inhibitors of Akt1 and Akt2: discovery of [1,2,4]triazolo[3,4-f][1,6]naphthyridines with potent and balanced activity

Bioorg Med Chem Lett. 2009 Feb 1;19(3):834-6. doi: 10.1016/j.bmcl.2008.12.017. Epub 2008 Dec 7.

Authors

Yiwei Li¹, Jun Liang, Tony Siu, Essa Hu, Michael A Rossi, Stanley F Barnett, Deborah Defeo-Jones, Raymond E Jones, Ronald G Robinson, Karen Leander, Hans E Huber, Sachin Mittal, Nicholas Cosford, Peppi Prasit

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., 770 Sumneytown Pike, WP14-2, West Point, PA 19486, USA. [email protected]

PMID: 19097777
DOI: 10.1016/j.bmcl.2008.12.017

Abstract

A series of [1,2,4]triazolo[3,4-f][1,6]naphthyridine allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been shown to have potent dual Akt1 and 2 cell potency. The representative compound 13 provided potent inhibitory activity against Akt1 and 2 in vivo in a mouse model.

MeSH terms

Allosteric Site
Animals
Chemistry, Pharmaceutical / methods*
Dose-Response Relationship, Drug
Drug Design
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / metabolism
Inhibitory Concentration 50
Lung / drug effects
Mice
Models, Chemical
Naphthyridines / chemistry*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / chemistry
Structure-Activity Relationship
Triazoles / chemistry*

Substances

ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Naphthyridines
Triazoles
Proto-Oncogene Proteins c-akt