Identification of a novel 3,5-disubstituted pyridine as a potent, selective, and orally active inhibitor of Akt1 kinase

Sheela A Thomas; Tongmei Li; Keith W Woods; Xiaohong Song; Garrick Packard; John P Fischer; Robert B Diebold; Xuesong Liu; Yan Shi; Vered Klinghofer; Eric F Johnson; Jennifer J Bouska; Amanda Olson; Ran Guan; Shayna R Magnone; Kennan Marsh; Yan Luo; Saul H Rosenberg; Vincent L Giranda; Qun Li

doi:10.1016/j.bmcl.2006.04.046

Identification of a novel 3,5-disubstituted pyridine as a potent, selective, and orally active inhibitor of Akt1 kinase

Bioorg Med Chem Lett. 2006 Jul 15;16(14):3740-4. doi: 10.1016/j.bmcl.2006.04.046. Epub 2006 May 5.

Affiliation

¹ Cancer Research, Department R47S, AP10 Abbott Laboratories, 100 Abbott Park Rd, Abbott Park, IL 60064, USA. sheela.thomas@abbott.com

PMID: 16678413
DOI: 10.1016/j.bmcl.2006.04.046

Abstract

Based on lead compounds 2 and 3 a series of 3,5-disubstituted pyridines have been designed and evaluated for inhibition of AKT/PKB. Modifications at the 3 position of the pyridine ring led to a number of potent compounds with improved physical properties, resulting in the identification of 11g as a promising, orally active Akt inhibitor. The synthesis, structure-activity relationship studies, and pharmacokinetic data are presented in this paper.

MeSH terms

3-Phosphoinositide-Dependent Protein Kinases
Administration, Oral
Animals
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology*
Mice
Protein Serine-Threonine Kinases / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Pyridines
3-Phosphoinositide-Dependent Protein Kinases
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt