Discovery of 2,3,5-trisubstituted pyridine derivatives as potent Akt1 and Akt2 dual inhibitors

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

doi:10.1016/j.bmcl.2004.12.062

Discovery of 2,3,5-trisubstituted pyridine derivatives as potent Akt1 and Akt2 dual inhibitors

Bioorg Med Chem Lett. 2005 Feb 15;15(4):905-9. doi: 10.1016/j.bmcl.2004.12.062.

Authors

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

Affiliation

¹ Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. [email protected]

PMID: 15686884
DOI: 10.1016/j.bmcl.2004.12.062

Abstract

This letter describes the discovery of a novel series of dual Akt1/Akt2 kinase inhibitors, based on a 2,3,5-trisubstituted pyridine scaffold. Compounds from this series, which contain a 5-tetrazolyl moiety, exhibit more potent inhibition of Akt2 than Akt1.

MeSH terms

Animals
Cell Membrane Permeability
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology
Humans
Inhibitory Concentration 50
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Proto-Oncogene Proteins
Pyridines
AKT1 protein, human
AKT2 protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt