Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension.

Abstract

Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

• Authors: Gui-Dong Zhu, Viraj B Gandhi, Jianchun Gong, Sheela Thomas, Keith W Woods, Xiaohong Song, Tongmei Li, R Bruce Diebold, Yan Luo, Xuesong Liu, Ran Guan, Vered Klinghofer, Eric F Johnson, Jennifer Bouska, Amanda Olson, Kennan C Marsh, Vincent S Stoll, Mulugeta Mamo, James Polakowski, Thomas J Campbell, Ruth L Martin, Gary A Gintant, Thomas D Penning, Qun Li, Saul H Rosenberg, Vincent L Giranda
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 13 Pg. 2990-3003 (Jun 28 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17523610 (Publication Type: Journal Article)

Chemical References

• 1-(5-(3-methyl-1H-pyrazolo(3,4-c)pyridin-5-yl)pyridin-3-yloxy)-3-(3-(trifluoromethyl)phenyl)propan-2-amine
• Indazoles
• Pyrazoles
• Pyridines
• Proto-Oncogene Proteins c-akt

Topics

• Administration, Oral
• Animals
• Biological Availability
• Crystallography, X-Ray
• Dogs
• Hypotension (chemically induced)
• Indazoles (adverse effects, chemical synthesis, pharmacology)
• Mice
• Models, Molecular
• Protein Conformation
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Purkinje Fibers (drug effects, physiology)
• Pyrazoles (adverse effects, chemical synthesis, pharmacology)
• Pyridines (adverse effects, chemical synthesis, pharmacology)
• Rats
• Stereoisomerism
• Structure-Activity Relationship