Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines

Hong Lin; Dennis S Yamashita; Ren Xie; Jin Zeng; Wenyong Wang; Jack Leber; Igor G Safonov; Sharad Verma; Mei Li; Louis Lafrance; Joseph Venslavsky; Dennis Takata; Juan I Luengo; Jason A Kahana; Shuyun Zhang; Kimberly A Robell; Dana Levy; Rakesh Kumar; Anthony E Choudhry; Michael Schaber; Zhihong Lai; Barry S Brown; Brian T Donovan; Elisabeth A Minthorn; Kristin K Brown; Dirk A Heerding

doi:10.1016/j.bmcl.2009.11.061

Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines

Bioorg Med Chem Lett. 2010 Jan 15;20(2):684-8. doi: 10.1016/j.bmcl.2009.11.061. Epub 2009 Dec 16.

Affiliation

¹ Oncology Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd., Collegeville, PA 19426, United States. [email protected]

PMID: 20006500
DOI: 10.1016/j.bmcl.2009.11.061

Abstract

The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.

MeSH terms

Aminopyridines / chemical synthesis
Aminopyridines / chemistry*
Aminopyridines / pharmacokinetics
Animals
Cell Line, Tumor
Cytochrome P-450 Enzyme System / metabolism*
Dogs
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / metabolism*
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Haplorhini
Humans
Mice
Phosphorylation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Pyrazines / chemical synthesis
Pyrazines / chemistry*
Pyrazines / pharmacokinetics
Pyridines / chemistry*
Rats
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Aminopyridines
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
KCNH2 protein, human
Protein Kinase Inhibitors
Pyrazines
Pyridines
Cytochrome P-450 Enzyme System
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Gsk3b protein, rat
Proto-Oncogene Proteins c-akt
Glycogen Synthase Kinase 3